KR20060013370A - Novel Piperidinylamino-thieno [2,3-d] pyrimidine Compounds - Google Patents

Abstract

The present invention relates to a 5-HT receptor antagonist. The novel piperidinylamino-thieno [2,3-d] pyrimidine compounds are shown in Formula I, and the synthesis and use of 5-HT receptors for the treatment of diseases delivered directly or indirectly by 5-HT receptors. Started. Such conditions include central nervous system diseases such as anxiety, depression, schizophrenia, neural tube damage, stroke and migraine headaches. Also included are methods of preparation and novel intermediates and pharmaceutically acceptable salts thereof.

Description

New piperidinylamino-thieno [2,3-d] pyrimidine compounds {NEW PIPERIDINYLAMINO-THIENO [2,3-D] PYRIMIDINE COMPOUNDS}

The present invention relates to serotonin (5-hydroxytrytamine or 5-HT) receptor modulators, eg agonists, and more particularly to novel piperidinylamino-thieno [ 2,3-d] pyrimidine compounds, and the use of such compounds in the treatment, control and / or prevention of physiological symptoms associated with serotonin action, such as vascular diseases such as angina, migraine, pulmonary hypertension and systemic hypertension It is about.

The serotonergic nervous system of the brain includes various disorders such as eating disorders, schizophrenia, neuralgia and addiction disorders; Depression, obsessive-compulsive disorder, panic disorder, anxiety, sexual dysfunction caused by the central nervous system, sleep disorders, food absorption disorders, alcoholism, pain, memory deficiencies, unipolar depression, dysthymia, bipolar depression, treatment resistant depression, medical illness Has been shown to affect various physiological effects in depression, panic disorder, obsessive compulsive disorder, eating disorders, social phobia, premenstrual discomfort mood, pulmonary hypertension and systemic hypertension.

5-HT receptor modulators such as antagonists, partial agonists or agents, and / or optional serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, fluvoxamine, sertraline, lorazepam, imipramine, citatal Roperam and notiptiline can be used to treat such diseases, as well as vasodilation, smooth muscle contraction, bronchial contraction, brain diseases such as vascular diseases such as angina and migraine; And neuropathological diseases, including Parkinson's disease and Alzheimer's disease. These compounds are also suitable for the control of pulmonary artery diseases including cardiovascular and pulmonary arterial hypertension and pulmonary artery fibrosis. These compounds also represent agents effective for regulating migraines, through the regulation of brain circulation. These compounds are also suitable for the prevention and control of the consequences of the development of cerebral infarction (stroke), such as stroke or cerebral ischemia. These compounds are also suitable for modulating diseases of the gastrointestinal tract, characterized by disorders of the serotonergic system and disorders of the metabolism of carbohydrates.

Trazodone modulates 5-HT action, and fluoxetine and fluvoxamine promote serotonergic neurotransmission through potential and selective inhibition of serotonin reuptake into presynaptic neurons. 3-chloroimipramine inhibits both 5-HT and norepinephrine reuptake. Other compounds of current interest as antidepressants include gemeldine, bupropion and nomifensin.

Type 2 serotonin inhibitors (5-HT ₂ ) mediate the action of various drugs used in the treatment of, for example, schizophrenia, eating disorders, cognition, depression, migraine, hypertension, anxiety, hallucinations, and gastrointestinal dysfunction. 5-HT _{2A , B or C} receptor subtypes show significant homology at the genetic, structural and functional levels, all of which are G-protein pair receptors (GPCRs). 5-HT _2A receptors were found at high density in the cerebral cortex and neuronal regions and at low density in the hippocampus, striatum, other cerebral regions, platelets and blood vessels and uterine smooth muscle. The 5-HT _2B receptor is a mammalian peripheral tissue such as the heart, skeletal muscle and vascular muscle, adipose tissue, intestines, ovaries, uterus, testes, liver, lungs, interest, trachea, spleen, thymus, thyroid gland, prostate gland and salivary glands. In addition, it is widely distributed in the CNS.

For example, there is a need for selectivity, high affinity metabolic stability 5-HT receptor modulators with good bioavailability, CNS permeability and good pharmacokinetic properties in vivo.

Summary of the Invention

The present invention relates to the discovery of novel compounds that are 5-HT modulators such as antagonists and / or SSRIs, such as in the treatment of vascular diseases such as angina, migraine, pulmonary arterial hypertension and systemic hypertension. It can be used for the prevention or treatment of 5-HT-related conditions. In particular, it has been found that certain piperidinylamino-thieno [2,3-d] pyrimidine compounds are effective 5-HT receptor modulators and / or SSRIs. In an embodiment, such compounds include compounds of the formula and pharmaceutically acceptable salts and / or esters thereof:

Wherein R ₁ and R ₂ are independently hydrogen; Lower alkyl such as straight or branched C ₁ , C ₂ , C ₃ , C ₄ or C ₅ alkyl; C ₁ to C ₆ cycloalkyl or cycloheteroalkyl; Halogen, halo-substituted alkyl, including F, Cl, Br, I, such as CF ₃ , CF ₂ CF ₃ , CH ₂ CF ₃ ; Or R ₁ and R ₂ taken together form a C ₅ to C ₇ cycloalkyl, for example cyclohexyl or cycloheteroalkyl ring; Cy is a single or conjugated substituted or unsubstituted alicyclic ring such as cycloalkyl, or preferably an aromatic ring structure such as phenyl, naphthyl, diphenylmethyl; n is 0, 1, 2, 3, 4 or 5.

In embodiments, R ₁ may be H or —CH ₃ . In embodiments, R ₂ may be preferably lower alkyl, eg straight or branched C ₁ , C ₂ , C ₃ (eg iso- or tert-butyl), C ₄ or C ₅ alkyl. . R ₁ and R ₂ may together preferably form a cyclohexyl ring. The linking group _denoted by () _n is straight or branched.

Substituents in Cy may be lower alkyl such as methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl mono-, di- or tri-substituted phenyl, naphthyl or biphenyl; Alkoxy or aryloxy such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclopentyloxy; Halo such as fluoro, chloro, bromo and iodo; Amino, dimethylamino, nitro, cyano, carboxy, carboxy ester, carboxamide, N-alkylcarboxamide, N, N-dialkylcarboxamide, trifluoromethyl, trifluoromethoxy, tetrazolo, sul Phonyl, thiomethyl, thioethyl, phenylthio, 2,3-methylenedioxy and 3,4-methylenedioxy.

In another embodiment the compound of the invention comprises a compound of formula II and pharmaceutically acceptable salts and / or esters thereof:

Formula II

Wherein R ₁ and R ₂ are independently hydrogen; Lower alkyl such as C ₁ to C ₅ alkyl; C ₁ to C ₆ cycloalkyl or cycloheteroalkyl; Halogen, halo-substituted alkyl, including F, Cl, Br, I, such as CF ₃ , CF ₂ CF ₃ , CH ₂ CF ₃ ; Or R ₁ and R ₂ taken together form a C ₅ to C ₇ cycloalkyl or cycloheteroalkyl ring;

R ₃ and R ₄ are independently a single or conjugated substituted or unsubstituted aromatic ring structure such as phenyl, naphthyl, diphenylmethyl; (C ₁ -C ₆ ) alkyl, (C ₁ -C ₇ ) cyclohexyl, Ar,

R ₅ is H, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₆ ) cycloalkyl, halogen substituted alkyl, NH ₂ , NHMe, NMe ₂ , NHEt, NH (Et) ₂ , NH (Pr), N (Pr) ₂ and n is 0, 1, 2, 3, 4 or 5.

The compounds of the invention may also be 5-HT receptor antagonists, e.g., 5-HT _2A, 5-HT ₂ receptor antagonist is preferably a 5-HT _2B receptor antagonist comprising a _{B or C} receptor.

In another embodiment the compounds of the invention also contain a 5-HT receptor moiety such as a 5-HT ₂ receptor moiety comprising a 5-HT _{2A , B or C} receptor and preferably a 5-HT _2B receptor moiety. May be an agent.

In another embodiment the compound of the present invention may be a 5-HT receptor agonist such as a 5-HT ₂ receptor agonist comprising a 5-HT _{2A , B or C} receptor and preferably a 5-HT _2B receptor agonist. .

Another aspect of the invention is a pharmaceutical composition comprising, in a mammal suffering from depression, an amount of a compound of formula (I) effective to treat depression, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating depression in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula (I).

Another aspect of the invention is a pharmaceutical composition comprising, in a mammal suffering from central nervous system disease, an amount of a compound of formula (I) effective to treat central nervous system disease, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating central nervous system disease in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula (I).

Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound of formula (I) effective in treating a pulmonary hypertension in a mammal suffering from pulmonary arterial hypertension, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating pulmonary hypertension in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula (I).

Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound of formula (I) effective in treating a systemic hypertension in a mammal suffering from systemic hypertension, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating systemic hypertension in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula (I).

Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound of formula (I) effective to treat conditions associated with vascular diseases such as angina, migraine, pulmonary hypertension and systemic hypertension.

Another aspect of the invention is a method of treating a condition associated with vascular disease such as angina, migraine, pulmonary hypertension and systemic hypertension.

Methods of preparing compounds and novel intermediates are also included in the present invention.

The present invention also elicited a treatment method associated with serotonergic dysfunction or hyperfunction. As described above, the compounds of the present invention have antagonist activity at the 5-HT _2B receptor, which interferes with the negative feedback mechanism induced by the inhibition of serotonin reuptake, thereby enhancing the effect of the compounds on the serotonin reuptake inhibitory activity. This is expected.

Detailed description of the invention

Features and other details of the invention will be described in more detail with reference to the accompanying drawings, which will be described in the claims. It is to be understood that the specific embodiments described herein are for illustrative purposes only and do not limit the invention. The main features of the invention can be used in various embodiments without departing from the spirit of the invention. Unless otherwise specified, all parts and percentages are by weight.

Justice

For convenience, any terms used in the specification, the examples, and the appended claims are summarized as follows.

The term "5-HT receptor modulator" or "5-HT modulator" refers to 5-HT _{1A , B, C, D, E or F} ; 5-HT _{2A , B or C} ; And 5-HT ₁ , 5-HT ₂ , 5-HT ₃ , 5-HT ₄ , 5-HT ₅ , 5-HT ₆ or 5-, including subtypes of each receptor type, such as 5-HT _{5A or B} It includes compounds that have an effect on the HT ₇ receptor. The 5-HT modulator may be an agonist, partial agonist or antagonist.

The term "treatment" is meant to include any effect that improves symptoms, diseases, disorders, and the like, such as alleviation, reduction, control or elimination.

The term "alkyl" refers to saturated aliphatic groups such as straight chain alkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched chain alkyl groups (eg, isopropyl, tert- Butyl, isobutyl), cycloalkyl (e.g., cycloaliphatic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups . In addition, the term "alkyl" means including an alkyl group having an oxygen, nitrogen, sulfur or phosphorus atom which substitutes a carbon atom in one or more hydrocarbon backbones. In certain embodiments, straight or branched alkyl has up to 6 carbon atoms in the backbone (eg, C ₁ -C _{6 for} straight chains, C ₃ -C _{6 for} branched chains), more preferably 4 or less Has a carbon atom of. Likewise, preferred cycloalkyls have 3 to 8 carbon atoms in the ring structure, more preferably 5 to 6 carbons in the ring structure. "C ₁ -C ₆ " includes alkyl groups containing 1 to 6 carbon atoms.

The term "alkyl" also means including both "unsubstituted alkyl" and "substituted alkyl", the latter of which being substituted alkyl means an alkyl moiety having a substituent substituting hydrogen on one or more carbons of the hydrocarbon backbone. do. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcar Carbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (alkylamino, dialkyl Amino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, Arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic Or it may comprise a heterocyclic aromatic moiety. Cycloalkyls can be further substituted, for example, with the substituents described above. "Alkylaryl" or "aralkyl" moiety is alkyl substituted with aryl (eg, phenylmethyl (benzyl)). "Alkyl" also includes side chains of natural or synthetic amino acids.

The term "aryl" refers to a "conjugated" or polycyclic ring having one or more aromatic rings, as well as five or six membered "unconjugated" or monocyclic aromatic groups which may contain 0-4 heteroatoms. It is meant to include groups having aromaticity, including phosphorus. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyridine Midine and the like. The term "aryl" also refers to multicyclic aryl groups, such as tricyclic, double rings, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl , Quinoline, isoquinoline, napridine, indole, benzofuran, purine, benzofuran, deazapurin or indolizin. These aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycle", "heterocycle", "heteroaryl" or "heteroaromatic". The aromatic ring may be substituted as described above at one or more ring positions, such as halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkyl Carbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl , Phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (alkylcarbonylamino, arylcarbonylamino, Carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfony Earth, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (eg, tetralin, methylenedioxyphenyl).

The term "alkenyl" is similar in length and possible substitution to alkyl described above, but means to include different unsaturated aliphatic groups in that it contains one or more double bonds. For example, the term "alkenyl" refers to straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched alkenyl groups, cyclo Alkenyl (eg alicyclic) groups (eg cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups and cycloalkyl or cycloalkenyl substituted als It includes a kenyl group. In addition, the term "alkenyl" is meant to include alkenyl groups comprising oxygen, nitrogen, sulfur or phosphorus atoms that replace one or more carbon atoms in the hydrocarbon backbone. In certain embodiments, straight or branched alkenyl groups have up to 6 carbon atoms (eg, C ₂ -C _{6 for} straight chains and C ₃ -C _{6 for} branched chains) in the backbone. Likewise, cycloalkenyl groups have 3 to 8 carbon atoms in the ring structure, more preferably 5 to 6 carbons in the ring structure. The term "C ₂ -C ₆ " is meant to include alkenyl groups containing 2 to 6 carbon atoms.

The term "alkenyl" also means to include both "unsubstituted alkenyl" and "substituted alkenyl", the latter of which being substituted alkenyls having substituents that substitute for hydrogen on one or more carbons in the hydrocarbon backbone. Refers to the kenyl moiety. Such substituents include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkalcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylates, alkylcarbonyl, arylcarbonyl, alkoxy Carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (alkylamino, dialkylamino, aryl Amino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, Thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic It may comprise a heterocyclic aromatic moiety.

The term "alkynyl" means similar to the alkyls described above in length and possible substituents, but includes different unsaturated aliphatic groups in that they contain one or more triple bonds. For example, “alkynyl” refers to straight chain alkynyl groups (eg, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, decinyl), branched alkynyl groups and cycloalkyl or Cycloalkenyl substituted alkynyl groups. In addition, the term "alkynyl" means including an alkynyl group having an oxygen, nitrogen, sulfur or phosphorus atom that replaces one or more carbons in the hydrocarbon backbone. In certain embodiments, straight or branched alkynyl groups have up to 6 carbon atoms (eg, C ₂ -C _{6 for} straight chains and C ₃ -C _{6 for} branched chains) in the backbone. The term "C ₂ -C ₆ " is meant to include alkynyl groups containing 2 to 6 carbon atoms.

The term "alkynyl" also means including both "unsubstituted alkynyl" and "substituted alkynyl", the latter of which "substituted alkynyl" replaces hydrogen on one or more carbon atoms of the hydrocarbon backbone. Refers to an alkynyl moiety having a substituent. Such substituents include, for example, alkyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxy Carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (alkylamino, dialkylamino, aryl Amino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, Thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic It may comprise a heterocyclic aromatic moiety.

Unless otherwise specified, the term "lower alkyl" includes alkyl groups as defined above, but includes alkyl groups having from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, in the backbone structure. I mean. The terms "lower alkenyl" and "lower alkynyl" mean, for example, having a chain length of 2 to 5 carbon atoms.

The term "acyl" is meant to include compounds and moieties containing acyl radicals (CH ₃ CO-) or carbonyl groups. The term "substituted acyl" means that one or more hydrogen atoms are, for example, alkyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbon Carbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphineto, cyano, amino ( Alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhi Drill, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, hetero Means that the cycle including the reel, alkylaryl, or an aromatic or substituted by acyl heteroaromatic portion.

The term "acylamino" means that the acyl moiety includes a moiety bound to an amino group. For example, the term is meant to include alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The term "aroyl" is meant to include compounds or moieties having an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of the aroyl group include phenylcarboxy, naphthyl carboxy and the like.

The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" further include oxygen, nitrogen or sulfur atoms that replace one or more carbon atoms, such as oxygen, nitrogen or sulfur atoms, of the hydrocarbon backbone. It includes an alkyl group as described.

The term "alkoxy" is meant to include substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. As an example of a substituted alkoxy group, a halogenated alkoxy group is mentioned. Alkoxy groups are alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, Aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphineato, cyano, amino (alkylamino, dialkylamino, arylamino, dia Arylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxyl Latex, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic Groups, such as the part can be replaced. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The term “heterocyclyl” or “heterocyclic group” means including a closed ring structure containing one or more heteroatoms, such as a 3-10 membered ring or a 4-7 membered ring. Heterocyclyl groups may be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinone and pyrrolidinone, sultam, sultone and the like do. The heterocyclic ring may be substituted at one or more positions with substituents as described above, such as halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkyl carbonyl , Alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (alkyl amino, dialkylamino, arylamino, diarylamino and alkylarylamino ), Acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfony Earth, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or aromatic or heteroaromatic moieties.

The term "thiocarbonyl" or "thiocarboxy" is meant to include compounds and moieties containing carbon linked to a sulfur atom by a double bond.

The term "ether" is meant to include compounds or moieties containing oxygen bonded to two different carbon atoms or heteroatoms. For example, the term is meant to include "alkoxyalkyl" which refers to an alkyl, alkenyl or alkynyl group covalently bonded to an oxygen atom covalently bonded to another alkyl group.

The term "ester" is meant to include compounds and moieties containing carbon or hetero atoms bonded to an oxygen atom bonded to carbon of a carbonyl group. The term "ester" is meant to include alkoxycarboxyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl and the like. Alkyl, alkenyl or alkynyl groups are as defined above.

The term "thioether" is meant to include compounds or moieties containing sulfur atoms bonded to two different carbon or hetero atoms. Examples of thioethers include, but are not limited to, alkthioalkyl, alkthioalkenyl and alkthioalkynyl. The term "alkthioalkyl" is meant to include compounds having an alkyl, alkenyl or alkynyl group attached to a sulfur atom bonded to an alkyl group. Similarly, the terms "alkthioalkenyl" and "alkthioalkynyl" refer to compounds or moieties in which an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom covalently bonded to an alkynyl group.

The term "hydroxy" or "hydroxyl" is -OH or -O ^- means that include a group having a.

The term "halogen" is meant to include fluorine, bromine, chlorine, iodine and the like. The term "perhalogenated" generally refers to a moiety in which all hydrogen is replaced with a halogen atom.

The term "polycyclyl" or "polycyclic radical" refers to two or more identical cyclic rings (eg, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, in which two or more carbons are shared in two adjacent rings). And / or heterocyclyl). Rings joined through non-adjacent atoms are referred to as "crosslinked" rings. Each ring in the polycyclic ring is substituted as described above, such as halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxy Carbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, Phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (alkylcarbonylamino, arylcarbonylamino, carbon Barmoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulf Ponamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or aromatic or heteroaromatic moieties may be substituted.

The term "hetero atom" is meant to include atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus.

It should be noted that the structure of some of the compounds of the present invention includes asymmetric carbon atoms. Thus, unless specified otherwise, it is to be understood that isomers derived from such asymmetry (eg, all enantiomers and diastereomers) are included within the scope of the present invention. Such isomers can be obtained in nearly pure form by classical separation techniques and stereochemically controlled synthesis. In addition, the structures and other compounds and moieties discussed in this application include all tautomers thereof. Where appropriate, alkenes may comprise E- or Z-geometries.

The term "combination theraphy" (or "co-theraphy") administers the 5-HT modulator of the present invention and one or more second agents, the second agent co-acting with these therapeutic agents. By means of administering as part of a particular therapeutic regimen to provide a beneficial effect from. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic synergies resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination is usually carried out over a limited time period (typically minutes, hours, days or mainly depending on the form of the combination selected). Although not common, it is to be understood that “combination therapy” includes the administration of two or more of these therapeutic agents as part of a separate monotherapy regimen that results in the formation or combination of the present invention by chance. "Combination therapy" includes the administration of these therapeutic agents in a sequential manner, that is, the administration of each therapeutic agent at different times, as well as the simultaneous administration of these or two or more of these therapeutic agents in a simultaneous manner. You have to understand. Nearly simultaneous administration can be achieved, for example, by administering to the patient a single capsule having a fixed ratio of each therapeutic agent, or by administering a plurality of single capsules for each therapeutic agent to the patient. Sequential or near simultaneous administration of each therapeutic agent may be by any suitable route, including but not limited to oral administration, intravenous administration, intramuscular administration and direct absorption through mucosal tissue. The therapeutic agent may be administered by the same route or by different routes. For example, the first therapeutic agent of a selected combination may be administered by intravenous injection, while the remaining therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. The order in which the agents are administered is not critical. “Combination therapy” may also include administering a therapeutic agent as described above in further combination with other biologically active ingredients and non-drug therapies (eg, surgery or radiation therapy). If the combination therapy further comprises a non-drug treatment, the non-drug treatment can be carried out at any suitable time so long as the beneficial effect from the joint action of the combination of the therapeutic and the non-drug treatment is achieved. For example, where appropriate, the beneficial effect is still achieved even when the non-drug treatment is temporarily removed from administration of the therapeutic agent for several days or weeks.

The term "anionic group" as used herein refers to a group that is negatively charged at physiological pH. Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate or phosphorothioate, or functional equivalents thereof. A “functional equivalent” of anionic groups is to be understood to include bioisosteres such as bioisosteres of carboxylate groups. Bioisotopes include both classical and non-classical isotope equivalents. Classical and nonclassical biological isotopes are known in the art (Silverman, RB The Organic Chemistry of Drug Design and Drug Action , Academic Press, Inc. San Diego, Calif., 1992, pp. 19-23). See particularly preferred anionic groups are carboxylates.

The term “heterocyclic group” should be understood to include a ring-closure structure in which one or more atoms in the ring are atoms other than carbon, such as nitrogen or oxygen or sulfur. Heterocyclic groups can be saturated or unsaturated, and heterocyclic groups such as pyrrole and furan can have aromatic properties. These include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. Heterocyclic groups, such as halogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxy, -CF ₃ , -CN, etc., in one or more component atoms Can be substituted.

The present invention relates to the invention of novel compounds which can be used for the treatment, prevention or treatment of 5-HT-related conditions, such as 5-HT modulators such as antagonists and / or SSRIs, in particular certain pipettes. It has been found that ridinylamino-thieno [2,3-d] pyrimidine compounds are effective for effective 5-HT receptor modulators and / or SSRIs. In an embodiment, such compounds include compounds of the formula and pharmaceutically acceptable salts and / or esters thereof:

Formula I

Wherein R ₁ and R ₂ are independently hydrogen; Lower alkyl such as straight or branched C ₁ , C ₂ , C ₃ , C ₄ or C ₅ alkyl; C ₁ to C ₆ cycloalkyl or cycloheteroalkyl; Halogen, halo-substituted alkyl, including F, Cl, Br, I, such as CF ₃ , CF ₂ CF ₃ , CH ₂ CF ₃ ; Or R ₁ and R ₂ taken together form a C ₅ to C ₇ cycloalkyl, for example cyclohexyl or cycloheteroalkyl ring; Cy is a single or conjugated substituted or unsubstituted alicyclic ring such as cycloalkyl, or a predetermined aromatic ring structure such as phenyl, naphthyl, diphenylmethyl; n is 0, 1, 2, 3, 4 or 5.

In embodiments, R ₁ may be H or —CH ₃ . In embodiments, R ₂ may be lower alkyl, eg straight or branched C ₁ , C ₂ , C ₃ (eg iso- or tert-butyl), C ₄ or C ₅ alkyl. . R ₁ and R ₂ may together preferably form a cyclohexyl ring. The linking group _denoted by () _n is straight or branched.

Substituents in Cy may be lower alkyl such as methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl mono-, di- or tri-substituted phenyl, naphthyl or biphenyl; Alkoxy or aryloxy such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclopentyloxy; Halo such as fluoro, chlorine, bromine and iodine; Amino, dimethylamino, nitro, cyano, carboxy, carboxy ester, carboxamide, N-alkylcarboxamide, N, N-dialkylcarboxamide, trifluoromethyl, trifluoromethoxy, tetrazolo, sul Phonyl, thiomethyl, thioethyl, phenylthio, 2,3-methylenedioxy and 3,4-methylenedioxy. n is 0, 1, 2 or 3 and R ₁ and R ₂ may be taken together to form a C ₆ cycloalkyl ring.

In another embodiment the compound of the invention comprises a compound of the formula and pharmaceutically acceptable salts and / or esters thereof:

Formula II

Wherein R ₁ and R ₂ are independently hydrogen; Lower alkyl such as C ₁ to C ₅ alkyl; C ₁ to C ₆ cycloalkyl or cycloheteroalkyl; Halogen, halo-substituted alkyl, including F, Cl, Br, I, such as CF ₃ , CF ₂ CF ₃ , CH ₂ CF ₃ ; Or R ₁ and R ₂ taken together form a C ₅ to C ₇ cycloalkyl or cycloheteroalkyl ring;

R ₃ and R ₄ are independently a single or conjugated substituted or unsubstituted aromatic ring structure such as phenyl, naphthyl, diphenylmethyl; (C ₁ -C ₆ ) alkyl, (C ₁ -C ₇ ) cyclohexyl, Ar,

R ₅ is H, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₆ ) cycloalkyl, halogen substituted alkyl, NH ₂ , NHMe, NMe ₂ , NHEt, NH (Et) ₂ , NH (Pr), N (Pr) ₂ and n is 0, 1, 2, 3, 4 or 5.

The compounds of the invention may also be 5-HT receptor antagonists, e.g., 5-HT _2A, 5-HT ₂ receptor antagonist is preferably a 5-HT _2B receptor antagonist comprising a _{B or C} receptor.

In another embodiment the compounds of the invention also contain a 5-HT receptor moiety such as a 5-HT ₂ receptor moiety comprising a 5-HT _{2A , B or C} receptor and preferably a 5-HT _2B receptor moiety. May be an agent.

In another embodiment the compound of the present invention may be a 5-HT receptor agonist such as a 5-HT ₂ receptor agonist comprising a 5-HT _{2A, B or C} receptor and preferably a 5-HT _2B receptor agonist. .

Another aspect of the invention is a pharmaceutical composition comprising, in a mammal suffering from depression, an amount of a compound of formula (I) effective to treat depression, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating depression in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula (I).

Another aspect of the invention is a pharmaceutical composition comprising, in a mammal suffering from central nervous system disease, an amount of a compound of formula (I) effective to treat central nervous system disease, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating central nervous system disease in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula (I).

Another aspect of the present invention is a pharmaceutical composition comprising an amount of a compound of formula (I) effective in treating a migraine in a mammal suffering from migraine, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating migraine in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of formula (I).

Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound of formula (I) effective to treat a condition associated with vascular disease such as angina, migraine, pulmonary hypertension and systemic hypertension.

Another aspect of the invention is a method for the treatment of vascular diseases such as angina, migraine, pulmonary arterial hypertension and systemic hypertension.

Methods of preparing compounds and novel intermediates are also included in the present invention.

The compounds of the present invention are effective for treating a wide variety of clinical conditions, such as serotonergic dysfunction or hyperactivity, characterized by an excess or absence of serotonin. Such symptoms include schizophrenia and other psychotic disorders, such as schizophrenic disorders, schizophrenia disorders, delusional disorders, short-term psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; Gastrointestinal disorders such as Crohn's disorder, eating disorders, neuralgia and addiction disorders; Obsessive-compulsive disorder, panic disorder, sexual dysfunction caused by central nervous system, sleep disorder, food absorption disorder, alcoholism, pain, memory deficit, unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, medical Depression from the disease, panic disorder, obsessive compulsive disorder, eating disorder, social phobia, premenstrual unpleasant mood disorder, mood disorders such as depression or more specifically depressive disorders such as single or recurrent major depressive disorder and dysthymic disorder, Or bipolar disorders such as bipolar I disorder, bipolar II disorder and circulatory disorder; Anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia with or without history of panic disorder, certain phobias, such as certain animal phobias, social phobia, post-traumatic stress disorder and acute stress disorder Disorders, and generalized anxiety disorders; Delirium, dementia and forgetfulness disorders and other cognitive or neurodegenerative disorders such as Alzheimer's disease, senile dementia, Alzheimer's type dementia, vascular dementia and other dementia, for example HIV disease, head trauma, Parkinson's disease, Huntington's chorea, Pick's disease (Pick's disease), dementia due to Creutzfeldt-Jakob disease or dementia due to various causes; Parkinson's disease and other extra-pyramidal movement disorders, such as medication-induced movement disorders, such as neuroleptic-induced Parkinson's disease, neuroleptic malignant syndrome, nerves Relaxant-induced acute dystonia, neuroleptic-induced acute dyspepsia, neuroleptic-induced delayed dyskinesia and drug-induced positional tremor; Substances caused by the use of alcohols, amphetamines (or amphetamine-like substances), caffeine, marijuana, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, sleeping pills and anti-anxiety agents Related disorders include substance related disorders including dependence and abuse, addiction, withdrawal, addiction delirium, withdrawal delirium, persistent dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down syndrome; Demyelinating diseases such as MS and ALS and other neuropathological diseases such as peripheral neuropathy such as diabetes and chemotherapy induced neuropathy, and post-therapy neuralgia, trigeminal neuralgia, segmental neuralgia or intercostal neuralgia, and other neuralgia; And cerebrovascular diseases due to acute or chronic cerebrovascular injury such as cerebral infarction, subarachnoid hemorrhage or cerebral edema.

The compounds of the present invention can be used for the treatment of the above symptoms, as well as vasodilation, smooth muscle contraction, bronchoconstiction, brain diseases such as vascular diseases such as vasodilation and blood flow disorders caused by vasodilation such as angina pectoris, vascular Headache, migraine and Raynaud's disease; Pulmonary arterial hypertension and systemic hypertension; And treatment of neuropathological diseases including Parkinson's disease and Alzheimer's disease; Regulation of the cardiovascular system; Prevention and control of the consequences of developing cerebral infarction (stroke), such as stroke or cerebral ischemia; And disorders of the serotonergic system (difficulty) and also characterized by disorders of carbohydrate metabolism (difficulty).

In addition, the compounds of the present invention may be used for stress related somatic disorders; Reflex sympathetic atrophy, such as appendix syndrome; Bladder dysfunction such as cystitis, bladder detrusor hyperreflection and urinary incontinence; And any of the foregoing symptoms, particularly pain or analgesia, which may contribute to or associated with pain transmission in migraine headaches.

It may be desirable to use a compound of the present invention in conjunction with another pharmacologically active agent to treat certain conditions. The compounds of the present invention may be provided with another therapeutic agent as a combination formulation for use simultaneously, separately or sequentially. Such combination preparations may be present, for example, in the form of twin packs.

A further aspect of the invention provides a compound of the invention with any or another 5-HT antagonist and / or SSRI, for example 5-HT ₃ antagonist such as ondansterone, granistron, trosetetron or jatiset Include in combination with the loan. In addition, the compounds of the present invention may be administered in combination with anti-inflammatory corticosteroids such as dexamethasone. In addition, the compounds of the present invention may be administered in combination with chemotherapeutic agents such as alkylating agents, anti-metabolic agents, mitotic inhibitors or cytotoxic antibiotics, as described above. In general, currently available dosage forms of known therapies are suitable for use in such combinations.

According to a further or alternative embodiment, the invention provides a compound of the invention for use in the manufacture of a medicament for the treatment or prevention of physiological disorders associated with excess or absence of serotonin, such as serotonergic dysfunction or hyperactivity. to provide.

The present invention also provides a method of treating or preventing a physiological disorder associated with an excess or absence of serotonin, such as serotonergic dysfunction or hyperactivity, wherein the method comprises a composition comprising a compound of the invention or a Administering the compound in an effective amount to a patient in need of such treatment or prevention.

In order to treat or prevent migraine headaches, the compounds of the present invention can be used in combination with other migraine medications, such as ergotamine or 5-HT ₁ agonists, in particular sumatriptan or riztriptan. Likewise, in order to treat behavioral hyperalgesia, the compounds of the present invention can be used in combination with antagonists of N-methyl-aspartate (NMDA), such as dizocilpin.

In addition, it will be appreciated that the compounds of the present invention may be used with antidepressants or anti-anxiety agents to treat or prevent depression and / or anxiety. Classes of antidepressants suitable for use in the present invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, reversible monoamine oxidase inhibitors, serotonin and noradrenaline reuptake inhibitors, corticosteroids Pin release factor (CRF) antagonists, β-adrenergic receptor antagonists, and non-forming antidepressants. Another class of antidepressants suitable for use in the present invention are noradrenaline and special serotonergic antidepressants such as multazapine. Suitable examples of noradrenergic reuptake inhibitors are amitripdylin, clomipramine, doxepin, imipramine, trimimipramine, amoxapine, decipramine, maprotilin, nortriptyline, reboxetine, pro Tryptiline and pharmaceutically acceptable salts thereof. Suitable examples of selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, sertraline and pharmaceutically acceptable salts thereof. Suitable examples of monoamine oxidase inhibitors include isocarboxazide, phenelzin, tranylcypromine, selegiline, and pharmaceutically acceptable salts thereof. Suitable examples of reversible monoamine oxidase inhibitors include moclobemide and pharmaceutically acceptable salts thereof. Suitable examples of serotonin and noradrenaline reuptake inhibitors include venlafaxine and pharmaceutically acceptable salts thereof. Suitable examples of corticotropin releasing factor (CRF) antagonists include the compounds described in international patent specifications WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Suitable examples of atypical antidepressants include bupropion, lithium, nefazoedone, sibutramine, trazodone, biloxazine and their pharmaceutically acceptable salts. Other antidepressants useful in the present invention include adenozolam, alaproclate, aminephtin, amitiliplin / chlordiazepoxide combination, atipamezole, azamiaserine, panzaprine, pefuralin, bifemellan , Binodalin, bifenamol, broparomin, bupropion, caroxazone, eryclamine, cyanopramine, simoxatone, citalopram, clemeprole, cloboxamine, dacefinyl, deanol, demexif Tilin, Dibenzepine, Dothiepyne, Droxidopa, Enepexin, Cetazolam, Etoperidone, Pemoxetine, Pengavin, Pezolamine, Flutracene, Idazoic Acid, Indalpine, Indeloxazine, Iprindol, Levoprotiline, ritoxetine, lofepramine, medipoxamine, metapramine, metallindol, myanserine, milnacipran, minafrine, multazapine, monotyreline, nebracetam, nepofam, nyala Mead, nomifensin, norfluoxetine, orotyrelin, oxaflozan, pinazepamine, pyrine , Pizotiline, litaserine, rolipram, cerchloramine, cetiphthyline, sibutramine, sulfbutamine, sulfrid, tenniloxazine, tozalinone, thymolybine, thianephthine, tiflucarbine, topena Sin, topisopam, toloxatone, geocetin, veraliprid, biquiline, gimelidine, zometapine and their pharmaceutically acceptable salts, and St. John's wort herb or St. John's wort (Hypericum perforatum) or extracts thereof. Preferred antidepressants include selective serotonin reuptake inhibitors, in particular fluoxetine, fluvoxamine, paroxetine, sertraline and pharmaceutically acceptable salts thereof.

Suitable classes of anti-anxiety agents for use in the present invention include benzodiazepines and 5-HT _1A agonists or antagonists, in particular 5-HT _1A partial agonists, and corticotropin releasing factor (CRF) antagonists. In addition to benzodiazepines, other suitable classes of anti-anxiety agents include, but are not limited to, nonbenzodiazepines soothing sleep drugs such as zolpidem; Mood stabilizing drugs such as clovazam, gabapentin, lamotrigine, lorlezole, oxcarbamezepine, styripentol and bibigatrine; And barbiturate. Benzodiazepines suitable for use in the present invention include alprazolam, chlordizepoxide, clonazepam, clolazate, diazepam, halazepam, lorezepam, oxazepamine, prazepam, and pharmaceutically acceptable salts thereof. Can be mentioned. Suitable examples of 5-HT _1A agonists or antagonists useful in the present invention specifically include the HT _1A partial agonists buspyrone, plesinoxane, gepyrone, ifapyrone, pindolol and pharmaceutically acceptable salts thereof. Another class of anti-anxiety agents useful in the present invention are compounds that possess muscarinic chloinergic acticity. Suitable compounds in this class include the m1 muscarinic cholinergic receptor antagonists such as those described in European patent specifications 0 709 093, 0 709 094 and 0 773 021 and in international patent specification WO 96/12711. Another class of anti-anxiety agents suitable for use in the present invention are compounds that act on ion channels. Compounds of this class include carbamasepine, lamotrigine, valproate, and pharmaceutically acceptable salts thereof.

Therefore, a further aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention and an antidepressant or anti-anxiety agent with one or more pharmaceutically acceptable carriers or excipients.

Antipsychotics suitable for use in combination with the compounds of the present invention include phenothiazines such as chlorpromazine, mesorizazine, thiolidazine, acetophenazine, flufenazine, perfenazine and trifluoroperazine. ; Thioxanthenes such as chlorprotisene or thiocytene; Heterocyclic dibenzazepines such as clozapine or olanzapine; Butyrophenones such as haloperidol; Diphenylbutylpiperidine, for example pimozide; And indole, for example molindolene. Other antipsychotics include roxapin, sulfide and risperidone. Antipsychotics when used in combination with a compound of the present invention are in the form of pharmaceutically acceptable salts, for example chlorpromazine hydrochloride, meridazine besylate, thiolidazine hydrochloride, acetophenazine maleate, flufenazine It is to be understood that hydrochloride, flufenazine enateate, flufenazine decanoate, trifluoroperazine hydrochloride, thiocetine hydrochloride, haloperidol decanoate, loxapine succinate and molindon hydrochloride may be present. Perphenazine, cloprotisen, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in rhinitis form.

Other classes of antipsychotics suitable for use in combination with the compounds of the present invention include dopamine receptor antagonists, in particular D2, D3 and D4 dopamine receptor antagonists and muscarinic m1 receptor agonists. An example of a D3 dopamine receptor antagonist is compound PNU-99194A. An example of a D4 dopamine receptor antagonist is PNU-101387. An example of a muscarinic m1 receptor agonist is wk nomelin.

Another class of antipsychotics suitable for use in combination with the compounds of the present invention are 5-HT _2A receptor antagonists, examples of which include MDL100907 and pananserine. Also suitable for use in combination with the compounds of the present invention are 5-HT _2A. And serotonin dopamine antagonists (SDA) which are believed to combine dopamine receptor antagonist activity, examples of which include olanzapine and ziprasidone.

Therefore, a further aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention and an antipsychotic agent in combination with one or more pharmaceutically acceptable carriers or excipients.

Compounds of the invention and other pharmacologically active agents can be administered to a patient simultaneously, sequentially or in combination. When using the combinations of the invention, it is to be understood that the compounds of the invention and other pharmacologically active agents can be present in the same pharmaceutically acceptable carrier and administered simultaneously. They may be present in separate pharmaceutical carriers, such as conventional oral formulations that are taken simultaneously. The term "combination" also means when the compounds are provided in separate formulations and administered sequentially.

The compounds of the present invention can be administered to patients (animals and humans) in need of such treatment in dosages that provide optimal pharmaceutical efficacy. Dosages necessary for use in any specific application will depend on the specific compound or composition selected for each patient, as well as the route of administration, the nature of the condition being treated, the age and symptoms of the patient, the medication used concurrently or subsequently by the patient. It is to be understood that the specific diet may be varied and other factors of ordinary skill in the art will be appreciated, while at the same time the appropriate dosage will ultimately be made by a careful judgment of the attending physician.

In the treatment of symptoms associated with excessive or absent serotonin, such as serotonergic dysfunction or hyperactivity, suitable dosage levels are generally from about 0.001 mg / kg to 50 mg / kg (patient body weight) per day. It may be administered in a dose or in an ekghl dose. The dose level is preferably about 0.01 to about 25 mg / kg per day, more preferably about 0.05 to about 10 mg / kg per day. For example, in the treatment or prevention of central nervous system disease, suitable oral dose levels are preferably about 0.001 mg / kg to about 10 mg / kg per day, about 0.005 mg / kg to about 5 mg / kg per day, Particularly preferred is about 0.01 mg / kg to 1 mg / kg per day. The compound may be administered in a regimen of 1 to 4 times per day, preferably once or twice per day.

The amount of compound of the present invention required for use in any treatment depends not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the age and symptoms of the patient, and ultimately the thoughtfulness of the attending physician. It is important to understand that judgment is made.

Compositions and combination therapies of the present invention can be administered in combination with various pharmaceutical excipients, including stabilizers, carriers, and / or encapsulating agents, as described herein.

The aqueous composition of the present invention comprises an effective amount of the peptide of the present invention dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

The term "pharmaceutical or pharmacologically acceptable" means, as necessary, to include molecular practice and compositions that do not produce deleterious, allergic or other undesirable reactions when administered to an animal or human. The term "pharmaceutically acceptable carrier" is meant to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media or agents in pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, the use of such medium or agent in the therapeutic compositions is contemplated. In addition, auxiliary active ingredients may also be incorporated into the compositions.

For administration to humans, the formulation must meet the sterility, pyrogenicity, general safety and purity criteria required by the Food and Drug Administration (FDA) of the Biological Pharmaceutical Standard.

The compositions and combination therapies of the invention are then generally formulated for parenteral administration. For example, they are formulated for infusion via the intravenous route, intramuscular route, subcutaneous route, intralesional route or even intraperitoneal route. The preparation of the composition of the present invention or the aqueous composition containing the active ingredient or component is known to those skilled in the art in light of the disclosure of the present disclosure. Typically, such compositions can be prepared as injections, as liquid solutions or suspensions. In addition, solid forms suitable for use can be prepared so that solutions or suspensions can be prepared as soon as liquid is not added prior to injection. In addition, the formulation can also be emulsified.

Pharmaceutical forms suitable for use as injections include sterile aqueous solutions or dispersions; Preparations comprising sesame oil, peanut oil or aqueous polypropylene glycol; And sterile powders for the instant preparation of injectable solutions or suspensions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterias, molds.

Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared by appropriate mixing in water with surfactants such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under the general conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Therapeutic compositions or pharmacological compositions of the invention generally comprise an effective amount of the compound (s) in combination therapy, dissolved or dispersed in a pharmaceutically acceptable medium. Pharmaceutically acceptable media or carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. The use of such media or agents in pharmaceutically active substances is well known in the art. Supplementary active ingredients can also be incorporated into the therapeutic compositions of the invention.

The preparation of pharmaceutical or pharmacological compositions is known to those skilled in the art in light of the disclosure of the present disclosure. Typically, such compositions are as injections, liquid solutions or suspensions; As a solid form suitable for making into a solution in liquid or a suspension in liquid prior to injection; As a tablet or other solid suitable for oral administration; As a time release capsule; Or any other form commonly used, including creams, lotions, mouthwashes, inhalants, and the like.

Sterilized injectable solutions can be prepared by incorporating the active ingredient in an appropriate amount in a suitable solvent with the various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various active ingredients into a sterile vehicle which contains a basic suspension medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is a vacuum-drying and freeze-drying technique which yields any further desired ingredients with the powder of the active ingredient from that solution which has been previously sterilized filtered. .

Also contemplated are the preparation of more concentrated or highly concentrated solutions for intramuscular injection. In this regard, it is preferred to use DMSO as a solvent, which results in extremely fast penetration and thus delivers high concentrations of the active compound (s) or agent (s) in small areas.

It may also be very useful to use sterile preparations, such as saline cleaning solutions, by surgeons, physicians or nurses cleaning specific areas in the surgical field. In addition, the therapeutic preparations according to the invention may be reconstituted in the form of oral agents, or may be reconstituted with antibacterial agents. Inhalation forms are also contemplated. In addition, the therapeutic agents of the invention may be prepared in a form suitable for topical administration, such as in creams and lotions.

Suitable preservatives for use in such solutions include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like. Suitable buffers may include boric acid, sodium bicarbonate, potassium bicarbonate, sodium borate and potassium borate, sodium carbonate and potassium carbonate, sodium acetate, sodium diphosphate, and the like, and these buffers have a pH range of about pH 6 to pH 8, preferably It is present in an amount sufficient to maintain a pH range of about pH 7 to pH 7.5. Suitable isotonic agents may include dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic composition is in the range of 0.9 +/- 0.2%. Suitable antioxidants and stabilizers include sodium sulfite, sodium metasulfite, sodium thiosulfite, thiourea, and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petroleum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, Carboxymethyl cellulose etc. are mentioned.

When formulated, the therapy is administered in a pharmacologically effective amount in a manner compatible with the dosage formulation. The formulations are easily administered in various formulations, such as the types of injectable solutions described above, but can also be used in drug release capsules and the like.

In this regard, the volume of the composition to be administered and the quantification of the active ingredient depend on the host animal to be treated. The precise amount of active compound required for administration depends on the judgment of the practitioner and is specific to each individual patient.

The minimum volume of composition required to disperse the active compound is typically used. In addition, the regimen suitable for administration varies, but is typical by first administering the compound, monitoring the results, and then providing additional controlled dosages in additional periods. For example, for parenteral administration, an aqueous solution that is properly buffered and isotonic if necessary is prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration. One dose is dissolved in 1 mmol of isotonic NaCl solution, which may be added in 1000 mmol of a hypodermolysis fluid or injected into the proposed injection site (eg, Remington's Pharmaceutical Sciences 15th). Edition, pages 1035-1038 and 1570-1580).

In certain embodiments, the active compound can be administered orally. This is generally contemplated in the case of preparations that have been resistant to or have become resistant to proteolysis by digestive enzymes. Such compounds include chemically designed or modified agents; Right turn peptides; And peptide and liposome formulations of release capsules over time that can avoid peptidase and ligase degradation.

Pharmaceutically acceptable salts include acid addition salts and are formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid and the like. In addition, salts formed by free carboxyl groups can also be derived from inorganic bases such as sodium, potassium, ammonium, calcium or iron hydroxides, and organic bases such as isopropylamine, trimethylamine, histimine, procaine and the like. have.

The carrier may also be a solvent or a dispersion medium, which contains, for example, water, ethanol, polyols (eg glycerol, propylene glycol, liquid polyethylene glycols, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of microbial action can be induced by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be induced by using absorption delaying agents, such as aluminum monostearate and gelatin, in the composition.

Sterile injectable solutions are prepared by incorporating the active compound together with various other ingredients enumerated above in a suitable suitable solvent and, if necessary, by filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients in a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of using sterile powders in the preparation of sterile injectable solutions, the preferred method is a vacuum-drying technique or a lyophilization technique which yields not only the powder of the active ingredient but also any further desired components from the solution which has been previously sterilized filtered. to be.

Also contemplated is the preparation of more concentrated or highly concentrated solutions for direct injection, where the consideration of using DMSO as solvent results in extremely fast penetration resulting in the delivery of high concentrations of the active agent to small areas. .

In formulation, the solution is administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The formulations are easily administered in various formulations, such as the types of injectable solutions described above, but can also be used in drug release capsules and the like.

For parenteral administration in an aqueous solution, for example, the solution should be properly buffered if necessary, first of all making the liquid diluent isotonic with sufficient saline or glucose. Such specific aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, sterile aqueous media that can be used are known to those skilled in the art in light of the present disclosure.

In addition to compounds formulated for parenteral administration, such as intravenous or intramuscular administration, other pharmaceutically acceptable forms include, for example, tablets or other solids for oral administration; Liposome preparations; Release capsules over time; And any other form currently used, including creams.

Additional formulations suitable for other modes of administration include suppositories. For suppositories, conventional binders and carriers include, for example, polyalkylene glycols or triglycerides, which suppositories contain the active ingredient in the range of 0.5% to 10%, preferably 1% to 2%. It can be prepared from the mixture.

Oral formulations include such normally used excipients, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, nacral saccharin, cellulose, magnesium carbonate and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release preparations or powders.

In certain embodiments, the oral pharmaceutical composition comprises an inert diluent or an assimilable edible carrier, or can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into diet foods. You can. For oral therapy administration, the active compounds can be incorporated with excipients and used in the form of digestible tablets, oral tablets (oral tablets), troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% active compound. Of course, the percentages of the components and formulations may vary, typically from about 2% to about 75%, or preferably from 25% to 60% of the unit weight. The amount of active compound in such therapeutically useful compositions should be such that a suitable dose will be obtained.

The tablets, troches, pills, capsules and the like may also include the following: binders such as tracant gum, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrants such as corn starch, potato starch, alginic acid and the like; Glidants such as magnesium stearate; And sweetening agents such as sucrose, lactose or saccharin, or flavoring agents such as peppermint, winter green oil or cherry flavoring agent. If the dosage unit is a capsule, this capsule may contain a liquid carrier in addition to the above types of materials. Various other materials may be present as coatings or otherwise present to modify the physical form of the dosage unit. In practice, for example, tablets, pills or capsules may be coated with shellac, sugar or both substances. Syrups of elixirs may contain active compounds, sucrose as sweetener, methylparaben and propylparaben as preservatives, dyes and flavoring agents such as cherry or orange flavoring agents.

The pharmaceutical compositions of the present invention may be used in the form of pharmaceutical preparations, for example in solid, semisolid or liquid form, which forms the active ingredient for external, enteric or parenteral use of one or more compounds of the present invention. Mixed with an organic or inorganic carrier or excipient suitable for the formulation. This active ingredient can be combined, for example, with a pharmaceutically acceptable carrier which is generally nontoxic for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers that can be used are water, glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and for the preparation of the formulation. It may be other suitable carriers, may be in solid, semisolid or liquid form, and auxiliaries, stabilizers, thickeners and coloring agents may also be used. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or symptom of the disease.

When preparing a solid composition such as a tablet, the main active ingredient is a pharmaceutical carrier such as conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, It is mixed with dicalcium phosphate or gum and other pharmaceutical diluents such as water to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention or a nontoxic pharmaceutically acceptable salt thereof. When referring to such preformulated compositions as homogeneous, this means that the active ingredients are evenly distributed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 mg to about 500 mg of the active ingredient of the invention. Tablets or pills of the novel compositions may be coated or otherwise formulated to provide formulations that provide points of action for a long time. For example, tablets or pills may comprise internal dose components and external dose components, the latter component being in the form of an envelope on the electronic component. The two components can be separated by an enteric layer that performs the action of inhibiting degradation in the gastrointestinal tract, causing the internal components to move intact into the duodenum or to delay release. Various materials can be used in such enteric layers or coatings, including various polymeric acids, and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

Liquid forms in which the compositions of the present invention may be incorporated for oral or infusion administration may contain pharmaceutically acceptable oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or in elixirs as well as for intravenous use. Aqueous solutions containing suitable solubilizing or emulsifying agents and similar pharmaceutical vehicles, suitably flavored syrups, aqueous or oily suspensions, and emulsions. Suitable dispersing or suspending agents in the case of aqueous suspensions include synthetic or natural gums such as tracant, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions suitable for inhalation or insufflation include solutions and suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described above. The composition is preferably administered by oral or nasal breathing route for local or systemic effects. Compositions in preferred sterile pharmaceutically acceptable solvents may be nebulized using an inert gas. The nebulized solution may be breathed directly from the nebulizer, or the nebulizer may be attached to a face mask, tent or intermittent positive pressure breathing apparatus. Solutions, suspensions or powder compositions are preferably capable of oral or nasal administration from a device that delivers the formulation in a suitable manner.

In order to treat the above mentioned clinical and disease, the compounds of the present invention are oral, topical, parenteral, inhaled nebulization or rectal in a dosage unit formulation containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles. May be administered. The term parenteral, as used herein, means including subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques.

The process for preparing the compounds of the present invention is illustrated in the following example (s). The following examples are presented for the purpose of illustrating the invention, but are not intended to limit the scope or spirit of the invention.

Manufacture 1

A mixture of 2-amino-5-alkyl-4-aryl-thiophene-3-carboxylic acid ethyl ester 2 (1 mmol) and ammonium formic acid (1.5 mmol) in formamide (4 mL) was refluxed for 12 hours. And heated. Monitor by TLC while reaction time is terminated. After cooling the reaction mixture to room temperature, ice (50 g) is poured to obtain a creamy precipitate. The precipitate is collected by filtration and recrystallized from acetone / water to give 3, usually in a yield of 70-90%.

Manufacture 2

A mixture of 5-aryl-6-alkyl-thieno [2,3-d] pyrimidin-4-ol (3.7 mmol) 3, thionyl chloride (5.5 mL) and anhydrous DMF (0.5 mL) was added for 4 hours. Heated to reflux. The reaction mixture was cooled down and excess thionyl chloride was removed by vacuum distillation. 200 g of ice was added to the resulting residue and extracted with dichloromethane (3 x 100 mL). The mixed organic layer is dried (Na ₂ SO ₄ ) and concentrated. The product was purified by column chromatography (100% DCM) to give 4-chloro-5-aryl-6-alkyl-thieno [2,3-d] pyrimidine 4 in 80-95% yield.

Manufacture 3

Sodium triacetate at room temperature in a mixture of 4-Boc-amino piperidine 5 (10 mmol) and aromatic aldehyde 6 (10 mmol) in 40 mL of DCM or DCE (1,2-dichloroethane) under N ₂ atmosphere Toxic borohydride (15 mmol) was added followed by acetic acid (20 mmol). The resulting cloudy mixture was stirred for 16 hours at room temperature until all starting material was consumed. The reaction mixture was quenched by addition of aqueous NaHCO ₃ solution and the product was extracted with EtOAC. The organic extract was dried (Na ₂ SO ₄ ) and the solvent was evaporated to yield product 8 in 90-95% yield.

Manufacture 4

Add intermediate 7 (10 mmol) at room temperature to a mixture of 4-Boc-amino piperidine 5 (10 mmol) and diisopropylethylamine (30 mmol) in 30 mL CH ₃ CN under N ₂ atmosphere. It was. The resulting mixture was refluxed for 16 hours. The reaction mixture was quenched by addition of aqueous NaHCO ₃ solution and the product was extracted with EtOAC. The organic extract was dried (Na ₂ SO ₄ ) and the solvent was evaporated to yield product 8 in 80-94% yield.

Manufacture 5

Boc-protection of crude 4-Boc-aminobenzyl product 8 is removed by treatment with 25% TFA-DCM for 2 hours at room temperature or 2M HCl in Et ₂ O solution for 16-20 hours at room temperature. In both cases anhydrous Et ₂ 0 was added after the solvent was evaporated. The resulting precipitate is filtered, washed several times with anhydrous Et ₂ 0 and dried in vacuo to afford the corresponding 4-amino-1-benzyl piperidine salt 9. The free base is isolated or occurs in situ during the subsequent coupling step.

Manufacture 6

To a 4-amino-piperidine 5 (1 mmol) solution in acetonitrile (5 mL) under N ₂ is added diisopropyl ethylamine (4 mmol) and chloro-thienopyrimidine 4 (1 mmol). Was added. The resulting solution was heated to reflux for 24 to 48 hours (monitored by TLC). The solvent was evaporated and EtOAc (20 mL) was added to the resulting residue. Wash with aqueous NaHCO ₃ (10 mL) and brine (10 mL). The organic layer was dried (Na ₂ SO ₄ ), concentrated and purified by flash column chromatography on silica gel (1% MeOH in DCM) to give 11 in a yield of 55-60%.

Manufacture 7

A 10 (1 mmol) solution in anhydrous DCM (1 mL) was added 2M HCl in (10 mL) in ether at 0 ° C. and the mixture was stirred for 1 h at the same temperature. The precipitated product was filtered off, washed with anhydrous Et ₂ O and dried under vacuum to afford pure Compound 1 in 90-94% yield.

Manufacture 8

To a 10 (1m.mol) solution in dry EtOH (2ml) at room temperature was added maleic acid (1m.mol) in EtOH (5ml) and the mixture was stirred for 1 hour. The reaction mixture is diluted with ether (5 mL) and cooled at 0 ° C. for 6-8 h. The precipitated product was filtered off, washed with anhydrous Et ₂ 0 and dried under vacuum to afford pure Compound 1b in 70-95% yield.

Manufacture 9

To a solution of 1-Boc-4-amino-piperidine 12 (2 mmol) in acetonitrile (5 mL) under N ₂ is added diisopropyl ethylamine (4 mmol) and stirred at room temperature for 5 minutes. Chloride-thienopyrimidine 4 was added to the mixture and the contents were heated to reflux for 16 hours (monitored by TLC). The solvent is evaporated and EtOAc (20 mL) and water (10 mL) are added to the residue. The organic layer is dried (MgSO ₄ ) and concentrated to afford crude product. Flash column chromatography on silica gel (1% MeOH in DCM) gave pure product 13 in a yield of 80-85%.

Manufacture 10

Boc-protection of 13 was removed by treatment with 25% TFA-DCM for 2 hours at room temperature or 2M HCl in Et ₂ O solution for 16-20 hours at room temperature. In both cases, the solvent is evaporated and anhydrous Et ₂ O is added. The resulting precipitate was filtered, washed several times with anhydrous Et ₂ 0 and dried in vacuo to give salt 14 in 95-97% yield. The free base of interest was isolated or generated in situ during the subsequent coupling step.

Manufacture 11

To a mixture of 14 (10 mmol) and aldehyde 6 (10 mmol) in 40 mL of DCM or DCE (1,2-dichloroethane) under N ₂ atmosphere was added sodium triacetoxy borohydride (15 mmol) at room temperature. And acetic acid (20 mmol) was added. The resulting cloudy mixture was stirred at rt for 16 h until all starting material was consumed. The reaction mixture was quenched by addition of aqueous NaHCO ₃ solution and the product was extracted with EtOAC. The EtOAC extract was dried (MgSO ₄ ) and the solvent was evaporated to afford crude product. Purification or recrystallization by flash column on silica gel gave pure product 11 in 90-95% yield.

Manufacture 12

To a mixture of diisopropylethylamine (30 mmol) in 13 (10 mmol) and 30 mL CH ₃ CN under N ₂ atmosphere was added Intermediate 7 (10 mmol) at room temperature. The resulting mixture was refluxed for 16 hours. The reaction mixture was quenched by addition of aqueous NaHCO ₃ solution and the product was extracted with EtOAC. The organic extract was dried (Na ₂ SO ₄ ) and the solvent was evaporated to yield product 8 in 80-94% yield.

Example 1

N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6-isopropylthieno [2,3-d] pyrimidin-4-amine, mono malate

N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6-isopropylthieno [2,3-d] pyrimidine- according to the procedure described in Preparation 8 for the title compound. Prepared from 4-amine (38 mg, 0.095 mmol) (36 mg, 75%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.25 (s, 1H), 7.65 (bs, 1H), 7.35 (m, 2H), 7.25 (d, 2H), 6.05 (s, 2H), 4.20 (m, 3H), 3.30 (m, 2H), 3.00 (m, 2H), 2.10 (m, 2H), 1.80 (m, 2H), 1.30 (d, 6H). MS (ESI) m / z: Calculated value: 402.5; Measured value: 403.2 (M ⁺ +1).

Example 2

N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6-chlorothieno [2,3-d] pyrimidin-4-amine, mono malate

The title compound was obtained in 64% yield by the procedure described in Preparation 8. ¹ H NMR (400 MHz, MeOH-d ⁴ ): δ 8.33 (s, 1H), 7.46 (s, 1H), 7.18 (m, 3H), 6.23 (s, 2H, malate), 4.38 (m, 1H ), 4.30 (s, 2H), 3.51 (m, 2H), 3.16 (m, 2H), 2.31 (m, 2H), 1.93 (m, 2H); MS (ESI) m / z: Calcd for C ₁₈ H ₁₈ ClF ₂ N ₄ S: 395.09; Found: 395.0 (M ⁺ +1).

Example 3

N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6-isopropylthieno [2,3-d] pyrimidin-4-amine, dihydrochloride

The title compound was prepared by N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6-isopropylthieno [2,3-d] pyrimidine by the procedure described in Preparation 7. Prepared from -4-amine (100 mg, 0.25 mmol) (110 mg, 93%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.50 (s, 1H), 7.60 (s, 1H), 7.30 (m, 2H), 7.15 (m, 1H), 4.65 (m, 1H), 4.40 ( s, 2H), 3.65 (m, 2H), 3.30 (m, 3H), 2.35 (m, 2H), 2.15 (m, 2H), 1.40 (d, 6H). MS (ESI) m / z: Calculated value: 402.5; Measured value: 403.1 (M ⁺ +1).

Example 4

N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6-chlorothieno [2,3-d] pyrimidin-4-amine dihydrochloride

The title compound was obtained in 66% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, MeOH-d ⁴ ): δ 8.63 (s, 1H), 7.70 (s, 1H), 7.27 (d, 2H), 7.17 (s, 1H), 4.56 (s, 1H), 4.40 (s, 2H), 3.62 (d, 2H), 3.29 (d, 2H), 2.35 (d, 2H), 2.05 (m, 2H); MS (ESI) m / z: Calcd for C ₁₈ H ₁₈ ClF ₂ N ₄ S: 395.09; Found: 395.0 (M ⁺ +1).

Example 5

N- (1- (1- (3-fluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine dihydrochloride

The title compound was prepared by N- (1- (1- (3-fluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3-d] by the procedure described in Preparation 7. Prepared from pyrimidin-4-amine (77 mg, 0.186 mmol) (66 mg, 73%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.65 (s, 1H), 7.40 to 7.60 (m, 5H), 4.55 (m, 2H), 3.95 (d, 1H), 3.40 (d, 1H), 3.20 (m, 1H), 3.10 (m, 1H), 2.85 (d, 2H), 2.25 to 2.45 (m, 3H), 2.15 (m, 1H), 2.00 (m, 1H), 1.85 (d, 3H) , 1.00 (d, 6H). MS (ESI) m / z: calc. 412.57; Measured value: 413.1 (M ⁺ +1).

Example 6

N- (1- (1- (3,5-difluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine dihydro Chloride

The title compound was prepared by N- (1- (1- (3,5-difluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3 by the procedure described in Preparation 7. -d] prepared from pyrimidin-4-amine (125 mg, 0.29 m.mol) (77 mg, 53%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.65 (9s, 1H), 7.55 (s, 1H), 7.35 (m, 2H), 7.15 (m, 1H), 4.60 (m, 2H), 3.95 ( d, 1H), 3.45 (d, 1H), 3.05 to 3.25 (m, 2H), 2.85 (d, 2H), 2.40 (m, 1H), 2.30 (m, 2H), 2.00 (m, 1H), 1.80 (d, 3H), 1.00 (d, 6H). MS (ESI) m / z: calc .: 430.56; Found: 431.1 (M ⁺ +1).

Example 7

4-N- (3- (1- (3-fluorophenyl) ethylamino) propylamino) -5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] Pyrimidine, dihydrochloride

The title compound was prepared using 4N- (3- (1- (3-fluorophenyl) ethylamino) propylamino) -5,6,7,8-tetrahydro-benzo [4,5] by the procedure described in Preparation 7. Prepared from thieno [2,3-d] pyrimidine (262 mg, 0.76 m.mol) (186 mg, 54%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.60 (s, 1H), 7.45 (m, 1H), 7.35 (m, 2H), 7.15 (m, 1H), 4.45 9 (q, 1H), 3.80 (m, 2H), 2.80-3.10 (m, 6H), 2.15 (m, 2H), 1.95 (m, 2H), 1.65 (d, 3H). MS (ESI) m / z: calc .: 384.51; Found: 385.1 (M ⁺ +1).

Example 8

4N- (3- (3-fluorobenzylamino) propylamino) -5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine, dihydrochloride

The title compound was prepared using 4N- (3- (3-fluorobenzylamino) propylamino) -5,6,7,8-tetrahydro-benzo [4,5] thieno [2, by the procedure described in Preparation 7. 3-d] pyrimidine (145 mg, 0.39 m.mol) was prepared (105 mg, 61%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.65 (s, 1H), 7.50 (m, 1H), 7.35 (m, 2H), 7.10 (m, 1H), 4.25 (s, 2H), 3.90 ( t, 2H), 3.20 (t, 2H), 3.05 (m, 2H), 2.90 (m, 2H), 2.10 (m, 2H), 1.95 (m, 4H). MS (ESI) m / z: calc .: 370.49; Found: 371.1 (M ⁺ +1).

Example 9

N- (3- (1- (3-fluorophenyl) ethylamino) propyl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine, dihydrochloride

The title compound was prepared by N- (3- (1- (3-fluorophenyl) ethylamino) propyl) -6-isobutylthieno [2,3-d] pyrimidine-4- by the procedure described in Preparation 7. Prepared from amine (157 mg, 0.4 m.mol) (142 mg, 76%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.60 (s, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.15 (m, 1H), 4.45 (m, 1H), 3.80 ( m, 2H), 3.10 (m, 1H), 2.95 (m, 1H), 2.85 (d, 2H), 2.15 (m, 2H), 2.00 (m, 1H), 1.70 (d, 3H), 1.00 (d , 6H). MS (ESI) m / z: calc .: 386.53; Found: 387.1 (M ⁺ +1).

Example 10

N- (1- (1- (2,4,6-trifluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine , Dihydrochloride

The title compound was prepared using N- (1- (1- (1- (2,4,6-trifluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2 by the procedure described in Preparation 7. , 3-d] pyrimidin-4-amine (110 mg, 0.25 m.mol) (90 mg, 71%). ¹ H NMR (400 MHz, CD ₃ 0D): 8.05 (s, 1H), 7.60 (s, 1H), 7.15 (m, 2H), 5.00 (m, 1H), 4.60 (m, 1H), 3.65 to 3.90 (m, 2H), 3.10 to 3.35 (m, 2H), 2.85 (d, 2H), 2.10 to 2.45 (m, 4H), 2.00 (m, 1H), 1.90 (d, 3H), 1.05 (d, 6H ). MS (ESI) m / z: calc .: 448.55; Found: 449.1 (M ⁺ +1).

Example 11

N- (1- (1- (2,6-difluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine, di Hydrochloride

The title compound was prepared by N- (1- (1- (2,6-difluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3 by the procedure described in Preparation 7. -d] prepared from pyrimidin-4-amine (104 mg, 0.24 m.mol) (105 mg, 87%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.65 (s, 1H), 7.65 (m, 1H), 7.60 (s, 1H), 7.20 (t, 2H), 5.00 (m, 1H), 4.60 ( m, 1H), 3.90 (d, 1H), 3.70 (d, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.85 (d, 2H), 2.10 to 2.45 (m, 4H), 2.00 (m, 1 H), 1.90 (d, 3 H), 1.00 (d, 6H). MS (ESI) m / z: calc .: 430.56; Found: 431.2 (M ⁺ +1).

Example 12

N- (1- (cyclohexylmethyl) piperidin-4-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-amine, dihydrochloride

The title compound was obtained in 85% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, MeOH-d ⁴ ): δ 8.68 (s, 1H), 4.70 (m, 1H), 3.71 (d, 2H), 3.20 (m, 2H), 3.01 (d, 2H), 2.61 (s, 3H), 2.53 (s, 3H), 2.40-2.20 (m, 4H), 1.88-1.71 (m, 6H), 1.39-1.26 (m, 3H), 1.09 (m, 2H); MS (ESI) m / z: Calcd for C ₂₀ H ₃₁ N ₄ S: 359.23; Measured value: 359.2 (M ⁺ +1).

Example 13

N- (1- (3-fluorobenzyl) piperidin-4-yl) -6-chloro-5-methylthieno [2,3-d] pyrimidin-4-amine, dihydrochloride.

The title compound was purified by N- (1- (3-fluorobenzyl) piperidin-4-yl) -6-chloro-5-methylthieno [2,3-d] pyrimidine by the procedure described in Preparation 7. Prepared from -4-amine (119 mg, 0.3 m.mol) (98 mg, 70%). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.05 (s, 1H), 7.55 (m, 1H), 7.40 (m, 2H), 7.25 (m, 1H), 4.65 (m, 1H), 4.40 ( s, 2H), 3.65 (m, 2H), 3.25 (m, 2H), 2.65 (s, 3H), 2.35 (m, 2H), 2.15 (m, 2H). MS (ESI) m / z: calc .: 390.91; Measured value: 391.2 (M ⁺ +1).

Example 14

2-((4- (6-chloro-5-methylthieno [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) methyl) benzonitrile, dihydrochloride

The title compound was prepared in 2-((4- (6-chloro-5-methylthieno [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) by the procedure described in Preparation 7. Prepared from methyl) benzonitrile (100 mg, 0.25 m.mol) (94 mg, 80%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.70 (s, 1H), 7.95 (m, 2H), 7.85 (t, 1H), 7.75 (t, 1H), 4.70 (m, 1H), 4.60 ( s, 2H), 3.70 (d, 2H), 3.45 (m, 2H), 2.65 (s, 3H), 2.15 to 2.45 (m, 4H). MS (ESI) m / z: calc .: 397.92; Found: 398.1 (M ⁺ +1).

Example 15

N- (1- (2-methoxybenzyl) piperidin-4-yl) -6-chloro-5-methylthieno [2,3-d] pyrimidin-4-amine, dihydrochloride

The title compound was purified by N- (1- (2-methoxybenzyl) piperidin-4-yl) -6-chloro-5-methylthieno [2,3-d] pyrimidine by the procedure described in Preparation 7. Prepared from -4-amine (115 mg, 0.29 m.mol) (129 mg, 95%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.90 (s, 1H), 7.50 (m, 2H), 7.15 (m, 1H), 7.05 (t, 1H), 4.65 (m, 1H), 4.40 ( s, 2H), 3.95 (s, 3H), 3.65 (m, 2H), 3.30 (m, 2H), 2.65 (s, 3H), 2.35 (m, 2H), 2.20 (m, 2H). MS (ESI) m / z: calc .: 402.94; Measured value: 403.3 (M ⁺ +1).

Example 16

N- (1- (3-fluorobenzyl) piperidin-4-yl) -6-chlorothieno [2,3-d] pyrimidin-4-amine, dihydrochloride

The title compound was obtained in 90% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, MeOH-d ⁴ ): δ 8.63 (s, 1H), 7.70 (s, 1H), 7.55 (dt, 1H), 7.39 (m, 2H), 7.28 (t, 2H), 4.56 (m, 1H), 4.39 (s, 2H), 3.62 (d, 2H), 3.29 (d, 2H), 2.35 (d, 2H), 2.04 (m, 2H); MS (ESI) m / z: Calcd for C ₁₈ H ₁₉ ClFN ₄ S: 377.1; Found: 377.2 (M ⁺ +1).

Example 17

[1- (3-Fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine, dihydrochloride

The title compound was prepared in 91% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.75 (s, 1H), 7.58 to 7.49 (m, 1H), 7.48 to 7.40 (m, 2H), 7.60 (t, 1H), 4.70 (m, 1H ), 4.39 (s, 2H), 3.61 (m, 2H), 3.30 (t, 2H), 3.24-3.12 (m, 2H), 2.99-2.81 (m, 2H), 2.41-2.29 (m, 4H), 2.02-1.91 (m, 4H). MS (ESI) m / z: Calculated value: 396.5; Measured value: 397.5 (M ⁺ +1).

Example 18

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (3-fluoro-phenylethyl) -piperi Din-4-yl] -amine, dihydrochloride

The title compound was prepared in 91% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.67 (s, 1H), 7.57 to 7.43 (m, 3H), 7.26 (t, 1H), 4.62 (m, 1H), 4.53 (q, 1H), 3.18 to 3.01 (m, 2H), 2.91 (t, 2H), 2.56 to 2.39 (m, 4H), 1.96 to 1.95 (m, 4H), 1.83 (d, 3H). MS (ESI) m / z: calc .: 410.5; Found: 411.2 (M ⁺ +1).

Example 19

N- {1- [1- (3-fluorophenyl) -ethyl] piperidin-4-yl} -5,6-dimethylthieno [2,3-d] pyrimidin-4-amine, dihydro Chloride

The title compound was prepared in 84% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.66 (s, 1H), 7.37 to 7.22 (m, 1H), 7.17 to 7.03 (m, 3H), 4.51 to 4.37 (m, 1H), 4.20 (q , 1H), 3.70 to 3.56 (m, 4H), 2.64 (s, 3H), 2.62 (s, 3H), 2.54 to 2.49 (m, 2H), 2.02 to 1.89 (m, 2H), 1.82 (d, 3H ). MS (ESI) m / z: Calculated value: 384.5; Found: 385.2 (M ⁺ +1).

Example 20

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (3,5-difluoro-phenylethyl) -Piperidin-4-yl] -amine, dihydrochloride

The title compound was prepared in 89% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.61 (s, 1H), 7.34 (m, 2H), 7.16 (m, 1H), 4.83 (bs, 3H), 4.63 (m, 1H), 4.56 ( m, 1H), 3.91 (m, 1H), 3.51-2.87 (m, 4H), 2.39-1.85 (m, 11H), 1.81 (d, 3H). MS (ESI) m / z: calc .: 428.5; Found: 429.1 (M ⁺ +1).

Example 21

[1- (2-Fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine, dihydrochloride

The title compound was prepared in 88% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.72 (s, 1H), 7.58 to 7.49 (m, 1H), 7.48 to 7.40 (m, 2H), 7.60 (t, 1H), 4.70 (m, 1H ), 4.39 (s, 2H), 3.61 (m, 2H), 3.30 (t, 2H), 3.04-3.12 (m, 2H), 2.89-2.91 (m, 2H), 2.21-2.39 (m, 4H), 1.91-2.02 (m, 4H), MS (ESI) m / z: Calculated value: 396.5; Measured value: 397.5 (M ⁺ +1).

Example 22

[1- (4-Fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine, dihydrochloride

The title compound was prepared in 89% yield by the procedure described in the preparation. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.71 (s, 1H), 7.54 to 7.40 (m, 2H), 7.22 to 7.14 (m, 2H), 4.64 (m, 1H), 4.32 (s, 2H ), 3.78 to 3.65 (m, 2H), 3.59 to 3.41 (m, 4H), 2.95 to 2.87 (m, 4H), 2.45 to 2.31 (m, 4H), 2.15 to 2.01 (m, 4H). MS (ESI) m / z: Calculated value: 396.5; Measured value: 397.5 (M ⁺ +1).

Example 23

[1- (3-Cyano-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine, dihydrochloride

The title compound was prepared in 91% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.70 (s, 1H), 8.02 (s, 1H), 7.96 (d, 1H), 7.90 (d, 1H), 7.70 (t, 1H), 4.71 ( m, 1H), 4.45 (s, 2H), 3.62 to 3.59 (m, 2H), 3.07 (t, 2H), 2.90 (t, 2H), 2.34 to 2.15 (m, 4H), 1.98 to 1.92 (m, 6H). MS (ESI) m / z: calc .: 403.5; Measured value: 404.3 (M ⁺ +1).

Example 24

N- {1- (3-fluorophenyl)-(ethyl) piperidin-4-yl} thieno [2,3-d] pyrimidin-4-amine, dihydrochloride

The title compound was prepared in 82% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.70 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.22 to 7.14 (m, 3H), 4.69 to 4.50 (m, 1H ), 4.52 (q, 1H), 3.50 to 3.37 (m, 4H), 2.39 to 1.85 (d, 2H), 1.80 (d, 3H). MS (ESI) m / z: calc .: 356.4; Found: 357.2 (M ⁺ +1).

Example 25

N- {1- [2- (3-fluorophenyl) propan-2-yl] piperidin-4-yl} (5,6,7,8-tetrahydro-benzo [4,5] thieno [ 2,3-d] pyrimidin-4-yl) -amine, dihydrochloride

The title compound was prepared in 91% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.55 (s, 1H), 7.43 to 7.29 (m, 3H), 7.22 (t, 1H), 4.42 (m, 1H), 3.18 to 3.01 (m, 2H ), 2.91 (t, 2H), 2.56 to 2.39 (m, 4H), 1.96 to 1.95 (m, 4H), 1,46 (s, 3H), 1.44 (s, 3H). MS (ESI) m / z: Calculated value: 424.5; Found: 425.1 (M ⁺ +1).

Example 26

N- {1- (3,5-difluorobenzyl) piperidin-4-yl} thieno [2,3-d] pyrimidin-4-amine, dihydrochloride

The title compound was prepared in 82% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.70 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.22 to 7.14 (m, 3H), 4.66 (m, 1H), 3.91 (s, 2H), 3.50 to 3.37 (m, 4H), 2.39 to 1.85 (d, 2H). MS (ESI) m / z: Calculated value: 360.42; Found: 361.1 (M ⁺ +1).

Example 27

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (2,4,6-trifluoro-phenyl ) (2-Methylpropyl) -piperidin-4-yl] -amine, dihydrochloride

The title compound was prepared in 85% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.69 (s, 1H), 7.44 to 7.31 (m, 1H), 7.20 to 7.01 (m, 3H), 4.66 to 4.55 (m, 1H), 4.47 to 4.50 (m, 1H), 3.30-3.17 (m, 4H), 2.66-2.42 (m, 4H), 2.20-1.87 (m, 9H), 1.85-1.70 (m, 2H), 1.22 (d, 3H), 1.20 (d, 2H). MS (ESI) m / z: Calculated value: 452.6; Measured value: 453.2 (M ⁺ +1).

Example 28

[1- (4-Methyl-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine- 4-yl) -amine, dihydrochloride

The title compound was prepared in 82% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.70 (s, 1H), 7.54 to 7.40 (d, 2H), 7.25 to 7.12 (d, 2H), 4.76 (m, 1H), 3.99 (s, 2H ), 3.03 to 2.89 (m, 4H), 2.50 (s, 3H), 2.29 to 2.17 (m, 2H), 2.12 to 2.02 (m, 2H), 1.99 to 1.89 (m, 4H), 1.73 to 1.50 (m , 4H). MS (ESI) m / z: calc .: 392.56; Measured value: 393.6 (M ⁺ +1).

Example 29

[1- (4-methoxy-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine, dihydrochloride

The title compound was prepared in 85% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.77 (s, 1H), 7.40 to 7.32 (d, 2H), 7.01 (d, 2H), 4.60 (m, 1H), 3.91 (s, 3H), 3.68 (s, 2H), 2.97 to 2.86 (m, 2H), 2.80 to 2.71 (t, 2H), 2.29 to 2.10 (m, 2H), 2.09 to 2.01 (m, 2H), 1.99 to 1.91 (m, 4H ), 1.72-1.60 (m, 4H). MS (ESI) m / z: Calculated value: 408.5; Measured value: 409.6 (M ⁺ +1).

Example 30

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (4-trifluoromethoxy-benzyl) -pi Ferridin-4-yl] -amine, dihydrochloride

The title compound was prepared in 80% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.80 (s, 1H), 7.49 to 7.36 (m, 4H), 3.99 (s, 2H), 3.12 to 2.99 (m, 1H), 2.98 to 2.78 (m , 4H), 2.31-2.20 (m, 2H), 2.15-1.98 (m, 2H), 1.90-1.78 (m, 4H), 1.76-1.66 (m, 4H). MS (ESI) m / z: calc .: 462.5; Found: 463.4 (M ⁺ +1).

Example 31

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (3,4-methylenedioxy-benzyl)- Piperidin-4-yl] -amine, dihydrochloride

The title compound was prepared in 75% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.80 (s, 1H), 7.45 (d, 1H), 7.22 to 7.01 (m, 2H), 6.02 (s, 2H), 4.69 (m, 1H), 3.77 (s, 2H), 3.21 to 3.04 (m, 2H), 2.98 (t, 2H), 2.43 to 2.22 (m, 2H), 2.25 to 2.01 (m, 2H), 1.99 to 1.87 (m, 4H), 1.65-1.60 (m, 4H). MS (ESI) m / z: Calculated value: 422.5; Found: 423.3 (M ⁺ +1).

Example 32

2- {4- (5,6-dimethylthieno [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl-methyl} benzonitrile, dihydrochloride

The title compound was prepared in 88% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.72 (s, 1H), 7.97 to 7.90 (m, 1H), 7.77 to 7.63 (m, 3H), 4.61 to 4.57 (m, 1H), 3.98 (s , 2H), 3.52 to 3.44 (m, 4H), 2.64 (s, 3H), 2.62 (s, 3H), 2.54 to 2.49 (m, 2H), 2.02 to 1.89 (m, 2H). MS (ESI) m / z: calc .: 377.5; Found: 378.1 (M ⁺ +1).

Example 33

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (2,6-difluorophenyl-ethyl) -Piperidin-4-yl] -amine, dihydrochloride

The title compound was prepared in 87% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.65 (s, 1H), 7.67 to 7.51 (m, 1H), 7.20 to 7.12 (t, 2H), 4.78 (q, 1H), 4.71 to 4.63 (m , 1H), 3.54 (t, 2H), 3.01 (t, 2H), 2.39 to 2.21 (m, 4H), 2.09 to 1.89 (m, 4H), 1.84 (d, 3H). MS (ESI) m / z: Calculated value: 428.5; Found: 429.1 (M ⁺ +1).

Example 34

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (2,4,6-trifluoro-phenyl Ethyl) -piperidin-4-yl] -amine, dihydrochloride

The title compound was prepared in 90% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.71 (s, 1H), 7.22 (t, 2H), 4.66 (q, 1H), 4.69 to 4.52 (m, 1H), 3.34 to 3.19 (m, 4H ), 2.69 to 2.41 (m, 4H), 2.12 to 1.99 (m, 8H), 1.80 (d, 3H). MS (ESI) m / z: calc .: 446 5; Found: 447.2 (M ⁺ +1).

Example 35

[1- (2,2-Diphenyl-ethyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] Pyrimidin-4-yl) -amine, dihydrochloride

Pure product was obtained by column chromatography (2% MeOH-DCM) in 46% yield. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.80 (s, 1H), 7.99 to 7.81 (m, 6H), 7.64 to 7.51 (m, 4H), 4.99 (m, 1H), 3.56 (m, 2H ), 3.01 to 2.92 (m, 1H), 2.90 to 2.74 (m, 4H), 2.33 to 2.20 (m, 2H), 2.01 to 1.90 (m, 2H), 1.87 to 1.80 (m, 4H), 1.69 to 1.52 (m, 4 H). MS (ESI) m / z: calc .: 468.6; Found: 469.8 (M ⁺ +1).

Example 36

(1-naphthalen-2-ylmethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine-4 -Yl) -amine, dihydrochloride

The title compound was prepared in 77% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.65 (s, 1H), 8.22 to 8.13 (m, 3H), 7.92 to 7.77 (m, 4H), 4.56 (m, 1H), 3.92 (s, 2H ), 3.14 to 3.00 (m, 1H), 2.94 to 2.82 (m, 4H), 2.20 to 2.01 (m, 2H), 2.00 to 1.90 (m, 2H), 1.89 to 1.74 (m, 4H), 1.60 to 1.49 (m, 4 H). MS (ESI) m / z: calc. 428. 5; Found: 429.8 (M ⁺ +1).

Example 37

[1- (4-Chloro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine- 4-yl) -amine, dihydrochloride

The title compound was prepared in 82% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.72 (s, 1H), 7.54 to 7.43 (m, 2H), 7.24 to 7.11 (m, 2H), 4.64 (m, 1H), 4.32 (s, 2H ), 3.78 to 3.65 (m, 2H), 3.59 to 3.41 (m, 4H), 2.95 to 2.87 (m, 4H), 2.45 to 2.31 (m, 4H), 2.15 to 2.01 (m, 4H). MS (ESI) m / z: calc .: 412.9; Measured value: 413.7 (M ⁺ +1).

Example 38

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (3,5-difluoro-phenylethyl) -Piperidin-4-yl] -amine, dihydrochloride

The title compound was prepared in 89% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.61 (s, 1H), 7.34 (m, 2H), 7.16 (m, 1H), 4.83 (bs, 3H), 4.63 (m, 1H), 4.56 ( m, 1H), 3.91 (m, 1H), 3.51-2.87 (m, 4H), 2.39-1.85 (m, 11H), 1.81 (d, 3H). MS (ESI) m / z: calc .: 428.5; Found: 429.1 (M ⁺ +1).

Example 39

N- {l- [1- (3-fluorophenyl) -ethyl] piperidin-4-yl} -5,6-dimethylthieno [2,3-d] pyrimidin-4-amine, dihydro Chloride

The title compound was prepared in 84% yield by the procedure described in Preparation 7. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.66 (s, 1H), 7.37 to 7.22 (m, 1H), 7.17 to 7.03 (m, 3H), 4.51 to 4.37 (m, 1H), 4.20 (q , 1H), 3.70 to 3.56 (m, 4H), 2.64 (s, 3H), 2.62 (s, 3H), 2.54 to 2.49 (m, 2H), 2.02 to 1.89 (m, 2H), 1.82 (d, 3H ). MS (ESI) m / z: calc .: 384.5; Found: 385.2 (M ⁺ +1).

Example 40

N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6-isopropylthieno [2,3-d] pyrimidin-4-amine

The title compound was prepared by the procedure described in Preparation 6, 4-chloro-6-isopropylthieno [2,3-d] pyrimidine (0.25 g, 1.18 mmol) and 1- (3,5-difluorobenzyl ) Was prepared from piperidin-4-amine (0.4 g, 1.77 mmol) (264 mg, 56%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.80 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.20 (m , 1H), 3.50 (s, 2H), 3.20 (m, 1H), 2.85 (m, 2H), 2.25 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H), 1.40 (d, 6H). MS (ESI) m / z: Calculated value: 402.5; Measured value: 403.1 (M ⁺ +1).

Example 41

N- (1- (3,5-difluorobenzyl) piperidin-4-yl) -6-chlorothieno [2,3-d] pyrimidin-4-amine

The title compound was obtained in 44% yield by the procedure described in Preparation 10 and Preparation 11. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.44 (s, 1H), 6.99 (s, 1H), 6.89 (d, 2H), 6.70 (t, 1H), 4.89 (d, 1H), 4.19 (m , 1H), 3.50 (s, 2H), 2.86 (d, 2H), 2.24 (t, 2H), 2.01 (d, 2H), 1.59 (m, 2H); MS (ESI) m / z: Calcd for C ₁₈ H ₁₈ ClF ₂ N ₄ S: 395.09; Found: 395.0 (M ⁺ +1).

Example 42

N- (1- (3-fluorobenzyl) piperidin-4-yl) -6-chloro-5-methylthieno [2,3-d] pyrimidin-4-amine

The title compound was prepared by 6-chloro-5-methyl-N- (piperidin-4-yl) thieno [2,3-d] pyrimidin-4-amine (95 mg, 0.336) by the procedure described in Preparation 12. m.mol) and 1- (bromomethyl) -3-fluorobenzene (70 mg, 0.37 m.mol) (119 mg, 91%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.10 (m, 2H), 6.95 (m, 1H), 5.30 (d, 1H), 4.05 (m , 1H), 3.55 (s, 2H), 2.95 (m, 2H), 2.50 (s, 3H), 2.25 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). MS (ESI) m / z: calc .: 390.91; Measured value: 391.2 (M ⁺ +1).

Example 43

2-((4- (6-chloro-5-methylthieno [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) methyl) benzonitrile

The title compound was prepared by 6-chloro-5-methyl-N- (piperidin-4-yl) thieno [2,3-d] pyrimidin-4-amine (95 mg, 0.336) by the procedure described in Preparation 12. m.mol) and 2- (bromomethyl) benzonitrile (73 mg, 0.37m.mol) (100 mg, 75%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.65 (d, 1H), 7.55 (m, 2H), 7.35 (m, 1H), 5.30 (d, 1H), 4.25 (m , 1H), 3.7 (s, 2H), 2.85 (m, 2H), 2.50 (s, 3H), 2.40 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m / z: calc .: 397.92; Measured value: 398.2 (M ⁺ +1).

Example 44

N- (1- (2-methoxybenzyl) piperidin-4-yl) -6-chloro-5-methylthieno [2,3-d] pyrimidin-4-amine

The title compound was prepared by 6-chloro-5-methyl-N- (piperidin-4-yl) thieno [2,3-d] pyrimidin-4-amine (95 mg, 0.336) by the procedure described in Preparation 12. m.mol) and 1- (chloromethyl) -2-methoxybenzene (58 mg, 0.37 m.mol) (115 mg, 85%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 6.95 (m, 1H), 6.85 (d, 1H), 5.35 (d , 1H), 4.25 (m, 1H), 3.85 (s, 3H), 3.60 (s, 2H), 2.90 (m, 2H), 2.50 (s, 3H), 2.35 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m / z: calc .: 402.94; Measured value: 403.2 (M ⁺ +1).

Example 45

N- (1- (3-fluorobenzyl) piperidin-4-yl) -6-chlorothieno [2,3-d] pyrimidin-4-amine

The title compound was obtained in 53% yield by the procedure described in Preparation 10 and Preparation 12. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.44 (s, 1H), 7.28 (dd, 1H), 7.09 (d, 1H), 7.08 (d, 1H), 6.98 (s, 1H), 6.95 (dt , 1H), 4.85 (d, 1H), 4.19 (m, 1H), 3.49 (s, 2H), 2.87 (d, 2H), 2.23 (dt, 2H), 2.09 (d, 2H), 1.60 (m, 2H); MS (ESI) m / z: Calcd for C ₁₈ H ₁₉ ClFN ₄ S: 377.1; Found: 377.2 (M ⁺ +1).

Example 46

N- (1- (1- (3-fluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine

The title compound was prepared by the procedure described in Preparation 6, 4-chloro-6-isobutylthieno [2,3-d] pyrimidine (250 mg, 1.1 mmol) and 1- (1- (3-fluorophenyl). ) Ethyl) piperidin-4-amine (0.49 mg, 2.2 m.mol) (291 mg, 64%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.75 (s, 1H), 5.00 (m , 1H), 4.10 (m, 1H), 3.45 (m, 1H), 3.00 (d, 1H), 2.80 (d, 1H), 2.70 (d, 2H), 1.85 to 2.25 (m, 5H), 1.45 to 1.65 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m / z: calc. 412.57; Found: 413.3 (M ⁺ +1).

Example 47

4N- (3- (3-fluorobenzylamino) propylamino) -5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine

The title compound was prepared by 6-isobutyl-N- (piperidin-4-yl) thieno [2,3-d] pyrimidin-4-amine (125 mg, 0.43 m.mol) by the procedure described in Preparation 12. ) And 1- (3,5-difluorophenyl) ethylmethanesulfonate (243 mg, 1.03 mmol) (127 mg, 69%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.75 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.15 (m , 1H), 3.45 (m, 1H), 2.95 (m, 1H), 2.80 (m, 1H), 2.70 (d, 2H), 2.20 (m, 4H), 1.95 (m, 1H), 1.55 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m / z: calc .: 430.56; Found: 431.1 (M ⁺ +1).

Example 48

To a mixture of intermediate 14 (10 mmol) and 3-fluorophenylacetophenone (10 mmol) in piperidine anhydrous DCM is added titanium isopropoxide (10 mmol) at room temperature and stirred for 24 hours. Diethylaluminum cyanide (10 mmol) was added to the solution and the mixture was stirred for 24 hours. The reaction was quenched by the addition of saturated aqueous NaHC0 ₃ solution, the organic layer was separated, dried and concentrated under reduced pressure to obtain cyano derivative 16 as a pale yellow powder in quantitative yield. Crude compound 16 was dissolved in anhydrous THF and MeMgBr (1 M, 12 mmol) was added at 0 ° C. and the reaction mixture was stirred at rt for 3 h. The mixture was poured into cold saturated NH ₄ Cl solution and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. Purification by flash column chromatography (2% MeOH-DCM) gave the title compound 17 (78%).

Example 49

4N- (3- (1- (3-fluorophenyl) ethylamino) propylamino) -5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine .

The title compound was purified by 5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine (172 mg, 0.76 m.mol) and N by the procedure described in Preparation 6. Prepared from -1- (1- (3-fluorophenyl) ethyl) propane-1,3-diamine (150 mg, 0.76 mmol) (291 mg, 100%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 5.90 (bs, 1H), 3.60 to 3.80 (m, 3H), 2.85 (m, 2H), 2.80 (m, 2H), 2.70 (m, 1H), 2.55 (m, 1H), 1.75-1.95 (m, 6H), 1.40 (d, 3H). MS (ESI) m / z: calc .: 384.51; Found: 385.1 (M ⁺ +1).

Example 50

4N- (3- (3-fluorobenzylamino) propylamino) -5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine

The title compound was prepared by 3N- (5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl) -1, by the procedure described in Preparation 3. Prepared from 3-diaminopropane (150 mg, 0.57 m.mol) and 3-fluorobenzaldehyde (70 mg, 0.57 mmol) (145 mg, 69%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.20 (bs, 1H), 3.80 (s , 2H), 3.70 (m, 2H), 2.80 (m, 6H), 1.80 (m, 6H), 1.70 (bs, 1H). MS (ESI) m / z: calc .: 370.49; Found: 371.1 (M ⁺ +1).

Example 51

N- (3- (1- (3-fluorophenyl) ethylamino) propyl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine

The title compound was prepared by the procedure described in Preparation 6, 4-chloro-6-isobutylthieno [2,3-d] pyrimidine (150 mg, 0.662 m.mol) and N-1- (1- (3- Prepared from fluorophenyl) ethyl) propane-1,3-diamine (130 mg, 0.662 m.mol) (157 mg, 62%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.40 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.75 (bs, 1H), 6.70 (s , 1H), 3.85 (m, 1H), 3.70 (m, 2H), 2.80 (m, 1H), 2.70 (d, 2H), 2.65 (m, 1H), 1.95 (m, 1H), 1.85 (m, 2H), 1.45 (d, 3H), 0.95 (d, 6H). MS (ESI) m / z: calc .: 386.53; Found: 387.1 (M ⁺ +1).

Example 52

N- (1- (1- (2,4,6-trifluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine

The title compound was prepared by the procedure described in Preparation 12. 6-isobutyl-N- (piperidin-4-yl) thieno [2,3-d] pyrimidin-4-amine (130 mg, 0.45 m.mol ) And 1- (2,4,6-trifluorophenyl) ethylmethanesulfonate (228 mg, 0.9 mmol) (110 mg, 55%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 6.75 (s, 1H), 6.65 (m, 2H), 4.95 (d, 1H), 4.15 (q, 1H), 4.05 (m , 1H), 3.00 (m, 2H), 2.70 (d, 2H), 2.20 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H), 1.55 (d, 3H), 1.25 to 1.65 ( m, 2H), 0.95 (d, 6H). MS (ESI) m / z: calc .: 448.55; Measured value: 449.2 (M ⁺ +1).

Example 53

N- (1- (1- (2,6-difluorophenyl) ethyl) piperidin-4-yl) -6-isobutylthieno [2,3-d] pyrimidin-4-amine

The title compound was prepared by 6-isobutyl-N- (piperidin-4-yl) thieno [2,3-d] pyrimidin-4-amine (130 mg, 0.45 m.mol) by the procedure described in Preparation 12. ) And 1- (2,6-difluorophenyl) ethylmethanesulfonate (211 mg, 0.9 mmol) (104 mg, 54%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.10 (m, 1H), 6.90 (m, 2H), 6.75 (s, 1H), 4.90 (d, 1H), 4.25 (q , 1H), 4.05 (m, 1H), 3.05 (m, 2H), 2.70 (d, 2H), 2.15 (m, 1H), 2.10 (m, 3H), 1.95 (m, 1H), 1.40 (d, 3H), 1.45-1.65 (m, 2H), 0.95 (d, 6H). MS (ESI) m / z: calc .: 430.56; Found: 431.2 (M ⁺ +1).

Example 54

N- (1- (cyclohexylmethyl) piperidin-4-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-amine

The title compound was obtained in 28% yield by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.36 (s, 1H), 5.36 (d, 1H), 4.22 (m, 1H), 2.80 (d, 2H), 2.44 (s, 3H), 2.41 (s , 3H), 2.21-2.09 (m, 7H), 1.79-1.45 (m, 6H), 1.20 (m, 4H), 0.88 (m, 2H). MS (ESI) m / z: Calcd for C ₂₀ H ₃₁ N ₄ S: 359.23; Measured value: 359.2 (M ⁺ +1).

Example 55

[1- (3-Fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine

The title compound was obtained in 72% yield by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 7.24 to 7.29 (m, 1H), 7.07 (d, 2H), 6.94 (t, 1H), 5.20 (s, 1H), 4.22 (m, 1H), 3.52 (s, 2H), 2.77 to 2.89 (m, 6H), 2.26 (t, 2H), 2.12 to 2.08 (m, 2H), 1.95 to 1.85 (m, 2H), 1.62 to 1.53 (m, 2 H). MS (ESI) m / z: Calculated value: 396.5; Measured value: 397.6 (M ⁺ +1).

Example 56

[1- (2-Fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine

The title compound was obtained in 58% yield by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.34 (s, 1H), 7.37 (t, 1H), 7.23 to 7.28 (m, 1H), 7.11 (t, 1H), 7.04 (t, 1H), 5.18 (d, 1H), 4.21 (m, 1H), 3.63 (s, 2H), 2.78 to 2.85 (m, 6H), 2.34 (t, 2H), 2.04 to 2.11 (m, 2H), 1.89 to 1.92 (m , 4H), 1.51-1.60 (m, 2H). MS (ESI) m / z: Calculated value: 396.5; Measured value: 397.6 (M ⁺ +1)

Example 57

[1- (2-Fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine

The title compound was obtained in 58% yield by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.34 (s, 1H), 7.37 (t, 1H), 7.23 to 7.28 (m, 1H), 7.11 (t, 1H), 7.04 (t, 1H), 5.18 (d, 1H), 4.21 (m, 1H), 3.63 (s, 2H), 2.78 to 2.85 (m, 6H), 2.34 (t, 2H), 2.04 to 2.11 (m, 2H), 1.89 to 1.92 (m , 4H), 1.51-1.60 (m, 2H). MS (ESI) m / z: Calculated value: 396.5; Measured value: 397.6 (M ⁺ +1).

Example 58

[1- (3-Cyano-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine

The title compound was obtained in 68% yield by the procedure described in Preparation 11. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 7.69 (s, 1H), 7.56 (d, 2H), 7.47 (t, 1H), 5.19 (d, 1H), 4.24 (m , 1H), 3.56 (s, 2H), 2.92 (t, 2H), 2.81 (t, 4H), 2.28 (t, 2H), 2.12-2.18 (m, 2H), 1.96-1.88 (m, 4H). MS (ESI) m / z: calc .: 403.5; Measured value: 404.3 (M ⁺ +1).

Example 59

N- {1- (3-fluorophenyl)-(ethyl) piperidin-4-yl} thieno [2,3-d] pyrimidin-4-amine

The title compound was obtained in 70% yield by the procedure described in Preparation 11. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 7.30 to 7.24 (m, 2H), 7.19 to 7.12 (m, 3H), 7.08 (t, 1H), 5.14 (d, 1H) , 4.60 to 4.50 (m, 1H), 4.12 (q, 1H), 3.50 to 3.37 (m, 4H), 2.18 to 2.04 (m, 2H), 1.78 to 1.69 (d, 2H), 1.40 (d, 3H) . MS (ESI) m / z: calc .: 356.4; Found: 357.2 (M ⁺ +1).

Example 60

N- {1- [2- (3-fluorophenyl) propan-2-yl] piperidin-4-yl} (5,6,7,8-tetrahydro-benzo [4,5] thieno [ 2,3-d] pyrimidin-4-yl) -amine

The title compound was prepared in 78% yield by the procedure described below (Scheme 3). ¹ H NMR (400 MHz, CD ₃ 0D): δ 7.94 (s, 1H), 7.29 to 7.21 (m, 3H), 6.83 (t, 1H), 3.81 to 3.72 (m, 1H), 3.08 to 3.01 (m , 2H), 2.81 (t, 2H), 2.36-2.20 (m, 4H), 1.96-1.95 (m, 4H), 1,31 (s, 3H), 1.30 (s, 3H). MS (ESI) m / z: calc .: 424.5; Found: 425.1 (M ⁺ +1).

Example 61

N- {1- (3,5-difluorobenzyl) piperidin-4-yl} thieno [2,3-d] pyrimidin-4-amine

The title compound was prepared in 82% yield by the procedure described in Preparation 10. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.70 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.22 to 7.14 (m, 3H), 4.66 (m, 1H), 3.91 (s, 2H), 3.50-3.37 (m, 4H), 2.39-1.85 (d, 2H). MS (ESI) m / z: Calculated value: 360. 42; Found: 361.1 (M ⁺ +1).

Example 62

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (2,4,6-trifluoro-phenyl ) (2-Methylpropyl) -piperidin-4-yl] -amine hydrochloric acid

The title compound was prepared in a yield of 55% by the procedure described in Preparation 11. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.30 (s, 1H), 7.33 to 7.25 (m, 1H), 7.01 to 6.93 (m, 3H), 5.16 (d, 1H), 4.19 to 4.10 (m, 1H), 3.60 to 3.50 (m, 1H), 2.82 to 2.60 (m, 4H), 2.32 to 2.02 (m, 4H), 1.88 to 1.75 (m, 9H), 1.59 to 1.40 (m, 2H), 1.22 ( d, 3H), 1.20 (d, 2H). MS (ESI) m / z: calc .: 452.6; Measured value: 453.2 (M ⁺ +1).

Example 63

{1- [1- (3-Fluoro-phenyl) -ethyl] -4-methyl-piperidin-4-yl}-(5,6,7,8-tetrahydro-benzo [4,5] thier No [2,3-d] pyrimidin-4-yl) -amine

The title compound was prepared by the procedure described in Preparation 12 (4-methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3- d] pyrimidin-4-yl) -amine (150 mg, 0.28 mmol) and methanesulfonic acid 1- (3-fluoro-phenyl) -ethyl ester (61.1 mg, 0.28 mmol) (97 mg, 81%). ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.38 (s, 1H), 7.20 (s, 1H), 6.89 to 6.79 (m, 3H), 3.91 (q, 1H), 2.80 to 2.74 (m , 4H), 2.20-2.09 (m, 2H), 1.09 (m, 2H), 1.89-1.85 (m, 4H), 1.55 (m, 4H), 1.31 (s, 3H); MS (ESI) m / z: calc .: 424.2; Found: 425.2 (M ⁺ +1).

Example 64

[1- (4-Methyl-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine- 4-yl) -amine

The title compound was prepared in 82% yield by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.24 to 7.22 (d, 2H), 7.19 to 7.02 (d, 2H), 5.24 (d, 1H), 4.26 (m, 1H) , 3.78 (s, 2H), 2.92 to 2.86 (m, 4H), 2.41 (s, 3H), 2.10 to 2.06 (m, 2H), 2.04 to 1.92 (m, 2H), 1.90 to 1.81 (m, 4H) , 1.69-1.57 (m, 4H). MS (ESI) m / z: calc .: 392.56; Measured value: 393.6 (M ⁺ +1).

Example 65

[1- (4-methoxy-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine -4-yl) -amine

The title compound was prepared in a yield of 65% by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 7.09 to 7 to 6.94 (d, 2H), 6.92 to 6.02 (d, 2H), 5.21 (s, 1H), 4.20 (m, 1H), 3.77 (s, 3H), 3.52 (s, 2H), 2.89 to 2.77 (m, 2H), 2.79 to 2.61 (t, 2H), 2.09 to 2.23 (m, 2H), 1.99 to 1.90 (m, 2H), 2.01 to 1.91 (m, 4H) , 1.65-1.55 (m, 4H). MS (ESI) m / z: Calculated value: 408.5; Measured value: 409.6 (M ⁺ +1).

Example 66

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (4-trifluoromethoxy-benzyl) -pi Ferridin-4-yl] -amine

The title compound was prepared in 42% yield by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.66 (s, 1H), 7.22 to 7.45 (m, 4H), 3.68 (s, 2H), 2.87 to 2.89 (m, 1H), 2.80 to 2.83 (m, 4H), 2.10-2.25 (m, 2H), 1.91-1.93 (m, 2H), 1.82-1.85 (m, 4H), 1.65-1.68 (m, 4H). MS (ESI) m / z: calc .: 462.5; Found: 463.4 (M ⁺ +1).

Example 67

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (3,4-methylenedioxy-benzyl)- Piperidin-4-yl] -amine

The title compound was prepared in a yield of 55% by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 6.94 (d, 1H), 6.88 to 6.59 (m, 2H), 5.99 (s, 1H), 5.20 (d, 1H), 4.21 (m, 1H), 3.50 (s, 2H), 2.97-2.84 (m, 2H), 2.81-2.71 (t, 2H), 2.29-2.13 (m, 2H), 2.05-1.96 (m, 2H), 1.91 ~ 1.82 (m, 4H), 1.62-1.50 (m, 4H). MS (ESI) m / z: calc .: 422.5; Found: 423.3 (M ⁺ +1).

Example 68

2- {4- (5,6-dimethylthieno [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl-methyl} benzonitrile

The title compound was prepared in a yield of 56% by the procedure described in Preparation 11. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 7.67 to 7.62 (m, 1H), 7.56 to 7.53 (m, 2H), 7.39 to 7.35 (m, 1H), 5.34 (d, 1H), 4.26 to 4.23 (m, 1H) , 3.74 (s, 2H), 2.92 to 2.84 (m, 4H), 2.44 (s, 3H), 2.41 (s, 3H), 2.14 to 2.09 (m, 2H), 1.66 to 1.56 (m, 2H). MS (ESI) m / z: Calculated value: 377.5; Found: 378.1 (M ⁺ +1).

Example 69

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (2,6-difluoro-phenylethyl) Piperidin-4-yl] -amine

The title compound was prepared in 52% yield by the procedure described in Preparation 11. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.30 (s, 1H), 7.26 to 7.18 (m, 1H), 6.80 (t, 2H), 5.17 (d, 1H), 4.24 (q, 1H), 4.15 ~ 4.11 (m, 1H), 2.90 (t, 2H), 2.70 (t, 2H), 2.36-2.11 (m, 4H), 2.09-1.87 (m, 4H), 1.59 (d, 3H). MS (ESI) m / z: calc .: 428.5; Found: 429.1 (M ⁺ +1).

Example 70

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (2,4,6-trifluorophenyl ethyl ) -Piperidin-4-yl] -amine

The title compound was prepared in a yield of 56% by the procedure described in Preparation 11. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.31 (s, 1H), 6.65 (t, 2H), 5.16 (d, 1H), 4.19 to 4.08 (m, 2H), 2.90 to 2.77 (m, 4H) , 2.33-2.07 (m, 4H), 1.89-1.85 (m, 4H), 1.60-1.56 (m, 4H), 1.40 (d, 3H). MS (ESI) m / z: calc .: 446.5; Found: 447.2 (M ⁺ +1).

Example 71

(1-naphthalen-2-ylmethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine-4 -Yl) -amine

The title compound was prepared in a yield of 35% by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.38 (s, 1H), 7.82 to 7.79 (m, 3H), 7.44 to 7.48 (m, 4H), 5.24 (d, 1H), 4.20 (m, 1H), 3.64 (s, 2H), 2.83 to 2.85 (m, 1H), 2.77 to 2.80 (m, 4H), 2.08 to 2.21 (m, 2H), 1.89 to 1.91 (m, 2H), 1.86 to 1.88 (m, 4H), 1.53 to 1.58 (m, 4H) . MS (ESI) m / z: calc .: 428.5; Found: 429.8 (M ⁺ +1).

Example 72

[1- (2,2-Diphenyl-ethyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] Pyrimidin-4-yl) -amine

The title compound was prepared in a yield of 46% by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.63 (s, 1H), 7.76 to 7.74 (m, 6H), 7.40 to 7.42 (m, 4H), 4.85 (m, 1H), 3.01 (m, 2H) , 2.85 to 2.87 (m, 1H), 2.81 to 2.84 (m, 4H), 2.11 to 2.24 (m, 2H), 1.90 to 1.92 (m, 2H), 1.81 to 1.84 (m, 4H), 1.66 to 1.69 ( m, 4H). MS (ESI) m / z: calc. 468.6; Found: 469.8 (M ⁺ +1).

Example 73

[1- (4-Chloro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine- 4-yl) -amine

The title compound was prepared in 82% yield by the procedure described in Preparation 6. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 7.27 to 7.13 (m, 2H), 7.03 to 6.89 (m, 2H), 4.21 (m, 1H), 3.89 (s, 2H), 3.21 to 3.14 (m, 2H), 2.90 ~ 2.74 (m, 8H), 2.02-1.92 (m, 4H), 1.64-1.51 (m, 4H). MS (ESI) m / z: calc .: 412.9; Measured value: 413.7 (M ⁺ +1).

Example 74

6-chloro-5-methyl-N- (piperidin-4-yl) thieno [2,3-d] pyrimidin-4-amine

The title compound was prepared by tert-butyl 4- (6-chloro-5-methylthieno [2,3-d] pyrimidin-4-ylamino) piperidine-1-carboxylate by the procedure described in Preparation 10. (611 mg, 1.6 m.mol) (289 mg, 64%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 5.30 (d, 1H), 4.25 (m, 1H), 3.15 (m, 2H), 2.85 (m, 2H), 2.55 (s , 3H), 2.15 (m, 2H), 1.95 (bs, 1H), 1.45 (m, 2H).

Example 75

3- (5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl) -1,3-diaminopropane

4-Chloro-5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine (0.5 g, 2.43 m. In 1,3-diaminepropane (5 mL). Mol) solution was heated at 80 ° C. for 1 day. After cooling to room temperature it was diluted with water (50 mL). The clear solution was cooled overnight at 0 ° C. The resulting solid was filtered and dried to give the title compound (0.3 g, 52%) as a brown solid. ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.20 (s, 1H), 3.65 (t, 2H), 2.95 (m, 2H), 2.80 (m, 4H), 1.80 to 2.00 (m, 6H). MS (ESI) m / z: calc. 262.37. Measured value: 263.1 (M ⁺ +1).

Example 76

6-isobutyl-N- (piperidin-4-yl) thieno [2,3-d] pyrimidin-4-amine

The title compound was purified by tert-butyl 4- (6-isobutylthieno [2,3-d] pyrimidin-4-ylamino) piperidine-1-carboxylate (900 mg) by the procedure described in Preparation 10. , 2.3 m.mol) (628 mg, 94%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.45 (s, 1H), 6.80 (s, 1H), 4.95 (d, 1H), 4.30 (m, 1H), 3.20 (m, 2H), 2.85 (m , 2H), 2.75 (d, 2H), 2.40 (bs, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.50 (m, 2H), 1.00 (d, 6H).

Example 77

{(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)}-piperidin-4-yl-amine

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 5.09 (d, 1H), 4.28 (m, 1H), 3.70 (t, 2H), 3.03 (t, 2H), 2.20 to 1.93 (m, 4H), 1.70-1.55 (m, 4H), 1.59 (m, 4H). MS (ESI) m / z: calc. 288.4; Measured value: 289.5 (M + 1).

Example 78

1- (5,6-dimethyl-thieno [2,3-d] pyrimidin-4-yl) -piperidin-4-yl-amine

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.60 (s, 1H), 6.90 (s, 1H), 3.80 (d, 2H), 3.00 (m, 5H), 2.49 (s, 3H), 2.47 (s, 3H), 2.00 to 1.80 (m, 4H) . MS (ESI) m / z: Calculated value: 262.3. Measured value: 263.2 (M + 1).

Example 79

Thieno [2,3-d] pyrimidin-4-yl) -piperidin-4-yl-amine

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.46 (s, 1H), 7.20 (dd, 2H), 3.10 (m, 5H), 1.60 (m, 4H). MS (ESI) m / z: MS (ESI) m / z: calculated value: 234.3: measured value: 235.1 (M + 1).

Example 80

(4-Methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl) -amine , diTFA salt

The title compound was prepared by the procedure described in Preparation 10. 4-methyl-4- (5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine-4- Prepared from monoamino) -piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.35 mmol) (179 mg, 97%). ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.51 (sb, 2H), 8.27 (s, 1H), 3.15 (m, 2H), 3.03 (m, 4H), 2.77 (m, 2H), 2.68 (m, 2H), 1.82 (m, 6H ), 1.51 (s, 3H); MS (SEI): m / z: Calculated Value: 302.2; Measured value: 303.1 (M ⁺ +1).

Example 81

tert-butyl-4- (6-chloro-5-methylthieno [2,3-d] pyrimidin-4-ylamino) piperidine-1-carboxylate

The title compound was purified by 4,6-dichloro-5-methylthieno [2,3-d] pyrimidine (425 mg, 1.94 m.mol) and tert-butyl 4-aminopiperidine by the procedure described in Preparation 9. Prepared from -1-carboxylate (582 mg, 2.9 m.mol) (611 mg, 82%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 5.25 (d, 1H), 4.35 (m, 1H), 4.30 (m, 2H), 3.00 (m, 2H), 2.55 (s , 3H), 2.15 (m, 2H), 1.45 (s, 9H), 1.35-1.55 (m, 2H).

Example 82

tert-butyl 4- (6-isobutylthieno [2,3-d] pyrimidin-4-ylamino) piperidine-1-carboxylate

The title compound was prepared by the procedure described in Preparation 9, 4-chloro-6-isobutylthieno [2,3-d] pyrimidine (300 mg, 1.32 m.mol) and tert-butyl 4-aminopiperidine- Prepared from 1-carboxylate (400 mg, 1.99 m.mol) (337 mg, 65%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.45 (s, 1H), 6.80 (s, 1H), 4.95 (m, 1H), 4.35 (m, 1H), 4.15 (m, 2H), 2.95 (m , 2H), 2.75 (d, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.45 (s, 9H), 1.40-1.50 (m, 2H), 0.95 (d, 6H).

Example 83

t-butyl 4- (6-chlorothieno [2,3-d] pyrimidin-4-ylamino) piperidine-1-carboxylate

t-butyl 4- (thieno [2,3-d] pyrimidin-4-ylamino) piperidine-1-carboxylate 13 (1.00 g, 3.00 mmol) and N-chlorosuccinimide (0.39 g, 3.00 mmol) was heated in 50 ml of acetic acid for 3 hours. After cooling at room temperature acetic acid is removed in vacuo and the remaining residue is separated in 1N NaOH and DCM. Purification by silica chromatography in 5% methanol in DCM and evaporation of DCM gave 0.78 g of t-butyl 4- (6-chlorothieno [2,3-d] pyrimidin-4-ylamino) piperidine- 1-carboxylate was collected. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.45 (s, 1H), 7.01 (s, 1H), 4.94 (d, 1H), 4.32 (m, 1H), 4.15 (m, 2H), 2.94 (m, 2H), 2.11 (m, 2H), 1.48 (s, 9H), 1.44 (m, 2H); MS (ESI) m / z: calc'd for C ₁₆ H ₂₁ ClN ₄ 0 ₂ S: 368.11; Measured value: 368.8 (M ⁺ +1).

Example 84

{(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl} -piperidin-4-yl-carbamic acid tert-butyl ester

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.51 (s, 1H), 5.12 (d, 1H), 4.32 (m, 1H), 3.94 (t, 2H), 3.17 (t, 2H), 2.26 to 2.19 (m, 4H), 1.78 to 1.69 (m, 4H), 1.61 (m, 4H), 1.43 (s, 9H). MS (ESI) m / z: Calculated value: 362.4; Found: 363.5 (M + 1).

Example 85

{1- (5,6-Dimethylthieno [2,3-d] pyrimidin-4-yl)}-piperidin-4-yl-carbamic acid tert-butyl ester

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 1H), 7.00 (s, 1H), 4.59 (br s, 1H), 3.80 (m, 3H), 3.15 (t, 2H), 2.49 ( s, 3H), 2.47 (s, 3H), 1.61 (m, 4H), 1.49 (s, 9H). MS (ESI) m / z: Calculated value: 388.5; Found: 389.4 (M + 1).

Example 86

Thieno [2,3-d] pyrimidin-4-yl) -piperidin-4-yl-carbamic acid tert-butyl ester

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.44 (s, 1H), 7.25 (dd, 2H), 4.45 (d, 1H), 3.80 (m, 1H), 3.24 (m, 2H), 2.18 (m , 2H), 1.50 (m, 2H), 1.49 (s, 9H). MS (ESI) m / z: Calculated value: 334.4; Found: 335.2 (M + 1).

Example 87

4-Methyl-4- (5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-ylamino) -piperidine-1-carboxyl Acid tert-butyl ester

The title compound was prepared by the procedure described in Preparation 9, 4-chloro-5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine (224 mg, 1 mmol). ) And 4-amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (235.4 mg, 1.1 mmol) (373.9 mg, 93%). ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.39 (s, 1H), 3.33 (m, 4H), 3.10 (m, 2H), 2.87 (m, 2H), 1.93 (m, 4H), 1.66 (m, 4H), 1.40 (s, 9H), 1.22 (s, 3H); MS (SEI): m / z: Calculated Value: 402.6; Measured value: 403.2 (M ⁺ +1).

Example 88

1- (3-Fluoro-benzyl) -piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in a yield of 90% by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.39 (bs, 2H), 7.48 (q, 1H), 7.39 to 7.22 (m, 3H), 4.27 (s, 2H), 3.60 to 3.20 (m, 4H), 3.08 (m, 1H), 2.18-2.08 (m, 2H), 1.90-1.79 (m, 2H). MS (ESI) m / z: calc .: 208.2; Measured value: 209.2 (M ⁺ +1).

Example 89

1- (2-Fluoro-benzyl) -piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in a yield of 85% by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.39 (bs, 2H), 7.55 to 7.39 (m, 2H), 7.30 to 7.22 (m, 2H), 4.31 (s, 2H), 3.51 to 3.42 ( m, 4H), 3.11 (m, 1H), 2.19-2.10 (m, 2H), 1.95-1.75 (m, 2H). MS (ESI) m / z: calc .: 208.2; Measured value: 209.2 (M ⁺ +1).

Example 90

1- (4-Chloro-benzyl) -piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in a yield of 86% by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.40 (bs, 2H), 7.69 (d, 2H), 7.42 (d, 2H), 4.26 (s, 2H), 3.33 to 2.91 (m, 1H) 3.10 to 2.22 (m, 4H), 2.21 to 1.89 (m, 4H). MS (ESI) m / z: Calculated value: 224.7; Measured value: 225.6 (M ⁺ +1).

Example 91

4- (4-Aminopiperidin-4-yl) -methyl-benzonitrile trifluoroacetate salt

The title compound was prepared in a yield of 86% by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.45 (bs, 2H), 7.61 to 7.50 (m, 2H), 7.44 to 7.32 (m, 2H), 4.29 (s, 2H), 3.62 to 3.49 ( m, 4H), 3.12 (m, 1H), 2.21-2.12 (m, 2H), 1.95-1.78 (m, 2H). MS (ESI) m / z: calc .: 208.2; Measured value: 209.2 (M ⁺ +1).

Example 92

1- (4-Toluyl) -piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in 87% yield by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.42 (bs, 2H), 7.68 (m, 2H), 7.28 (m, 2H), 4.21 (s, 2H), 3.2 (m, 1H) 3.08 ( m, 4H), 2.76 (s, 3H), 1.91-2.21 (m, 4H). MS (ESI) m / z: Calculated Value: 204.3; Measured value: 205.2 (M ⁺ +1).

Example 93

1-benzo [1,3] dioxol-5-ylmethyl-piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in a yield of 70% by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.36 (bs, 2H), 7.25 (s, 1H), 6.96 to 7.03 (m, 2H), 6.06 (s, 2H), 4.12 (s, 2H) , 3.35 (m, 1H), 3.22 (m, 2H), 2.93 (m, 2H), 1.96 to 2.1 (m, 4H). MS (ESI) m / z: calc .: 234.2; Found: 235.2 (M ⁺ +1).

Example 94

1- (4-methoxy-benzyl) -piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in 83% yield by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.44 (bs, 2H), 7.25 to 7.19 (d, 2H), 7.20 to 7.09 (d, 2H), 4.29 (s, 2H), 3.50 to 3.41 ( m, 4H), 3.17 (m, 1H), 2.14-2.06 (m, 2H), 1.93-1.70 (m, 2H). LC / MS (ESI) m / z: Calculated value: 220.6; Measured value: 221.4 (M ⁺ +1).

Example 95

1- (4-Trifluoromethoxy-benzyl) -piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in 63% yield by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.41 (bs, 2H), 7.39 to 7.23 (m, 2H), 7.22 to 7.10 (m, 2H), 4.33 (s, 2H), 3.49 to 3.35 ( m, 4H), 3.13 (m, 1H), 2.21-2.14 (m, 2H), 1.90-1.82 (m, 2H). LC / MS (ESI) m / z: calc'd: 274.1; Found: 275.3 (M ⁺ +1).

Example 96

1-naphthalen-2-ylmethyl-piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in 91% yield by the procedure described in Preparation 5. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.39 (bs, 2H), 8.11 (m, 1H), 7.96 (m, 3H), 7.69 (m, 1H), 7.59 (m, 1H), 7.06 (d, 1H), 4.40 (s, 2H), 3.43 (m, 1H), 3.08-3.17 (m, 4H), 1.7-1.9 (m, 4H). MS (ESI) m / z: calc .: 240.3; Measured value: 241.2 (M ⁺ +1).

Example 97

1- (2,2-diphenyl-ethyl) -piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in 42% yield by the procedure described in Preparation 5. LC / MS (ESI) m / z: Calcd: 280.4; Found: 281.3 (M ⁺ +1).

Example 98

tert-butyl-1- (2-fluorobenzyl) piperidin-4-yl-carbamate

The title compound was prepared in 92% yield by the procedure described in Preparation 4. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34-7.28 (m, 2H), 7.02-6.94 (m, 2H), 4.21 (brs, 1H), 3.55 (s, 2H), 3.13 (t, 2H) , 2.98 (t, 2H) 2.08 (t, 2H), 2.00-1.98 (m, 2H), 1.44 (s, 9H). MS (ESI) m / z: calc .: 308.8; Measured value: 309.7 (M ⁺ +1).

Example 99

tert-butyl-1- (3-fluorobenzyl) piperidin-4-yl-carbamate

The title compound was prepared in a yield of 90% by the procedure described in Preparation 4. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.22 to 7.10 (m, 3H), 7.02 to 6.90 (m, 1H), 4.11 (brs, 1H), 3.43 (s, 2H), 3.00 (t, 2H) , 2.92 (t, 2H) 2.02 (t, 2H), 1.98-1.87 (m, 2H), 1.43 (s, 9H). MS (ESI) m / z: calc .: 308.8; Measured value: 309.5 (M ⁺ +1).

Example 100

tert-butyl-1- (4-fluorobenzyl) piperidin-4-yl-carbamate

The title compound was prepared in 92% yield by the procedure described in Preparation 4. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.37 to 7.21 (m, 2H), 7.00 to 6.88 (m, 2H), 4.02 (brs, 1H), 3.39 (s, 2H), 3.00 (t, 2H) , 2.92 (t, 2H) 2.02 (t, 2H), 1.98-1.87 (m, 2H), 1.43 (s, 9H). MS (ESI) m / z: calc .: 308.8; Measured value: 309.9 (M ⁺ +1).

Example 101

1- (3,5-difluorobenzyl) piperidin-4-amine

The title compound was prepared from tert-butyl 1- (3,5-difluorobenzyl) piperidin-4-ylcarbamate (3.26 g, 10 m.mol) by the procedure described in Preparation 5 (1.92 g , 85%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 6.90 (m, 2H), 6.75 (m, 1H), 3.50 (s, 2H), 3.15 (m, 1H), 2.85 (m, 2H), 2.10 ( m, 2H), 1.85 (m, 2H), 1.50 (m, 2H). MS (ESI) m / z: calc. 226.27; Found: 227.1 (M ⁺ +1).

Example 102

1- (4-Fluoro-benzyl) -piperidin-4-ylamine trifluoroacetate salt

The title compound was prepared in 87% yield by the procedure described in Preparation 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.42 (bs, 2H), 7.68 (m, 2H), 7.28 (m, 2H), 4.21 (s, 2H), 3.2 (m, 1H) 3.08 ( m, 4H), 1.9 to 2.2 (m, 4H). MS (ESI) m / z: calc. 208.2; Measured value: 209.2 (M ⁺ +1).

Example 103

N1- (1- (3-fluorophenyl) ethyl) propane-1,3-diamine

The title compound was prepared from tert-butyl 3- (1- (3-fluorophenyl) ethylamino) propylcarbamate (1 g, 3.38 m.mol) by the procedure described in Preparation 10 (0.66 g, 100%). ). ¹ H NMR (400 MHz, CD ₃ 0D): δ 7.35 (m, 1H), 7.15 (m, 2H), 6.95 (m, 1H), 3.75 (q, 1H), 2.85 (m, 2H), 2.55 ( m, 1H), 2.45 (m, 1H), 1.75 (m, 2H), 1.35 (d, 3H). MS (ESI) m / z: calc .: 196.26; Measured value: 197.0 (M ⁺ +1).

Example 104

tert-butyl 3- (1- (3-fluorophenyl) ethylamino) propylcarbamate

Tert-butyl 3-aminopropylcarbamate (0.7 g, 4.05 m.mol) and 1- (3-fluorophenyl) ethanone (0.5) in titanium (IV) isopropoxide (1.8 mL, 6 m.mol) g, 3.6 m.mol) solution was stirred at room temperature for 3 hours. After dilution with methanol (10 mL) sodium borohydride (0.22 g, 5.76 m.mol) was carefully added and stirred for 10 minutes. The reaction mixture was quenched using 0.1 N NaOH (10 mL) solution. Filter with celite and wash with dichloromethane (2 × 20 mL). The organic layer is separated, dried over CaCl ₂ and evaporated to afford the title product as a thick liquid (1.07 g, 100%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 5.10 (bs, 1H), 3.75 (q, 1H), 3.15 (m , 2H), 2.55 (m, 1H), 2.45 (m, 1H), 1.60 (m, 2H), 1.45 (s, 9H), 1.35 (d, 3H). MS (ESI) m / z: calc .: 296.38; Found: 297.0 (M ⁺ +1).

Example 105

t-butyl 1- (cyclohexylmethyl) piperidin-4-ylcarbamate

The title compound was prepared in 81% yield by the procedure described in Preparation 3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.80. (bs, 1H), 3.71 (m, 1H), 3.63 (m, 2H), 2.53 (m, 2H), 2.43 (m, 2H), 2.00-1.61 (m, 9H), 1.44 (s, 9H), 1.23 (m, 4 H), 0.95 (m, 2 H); MS (ESI) m / z: Calcd for C ₁₇ H ₃₃ N ₂ 0 ₂ : 297.25; Found: 297.1 (M ⁺ +1).

Example 106

1- (cyclohexylmethyl) piperidin-4-amine, dihydrochloride

The title compound was prepared in a yield of 71% by the procedure described in Preparation 5. ¹ H NMR (400 MHz, MeOH-d ⁴ ): δ 3.69 (dt, 2H), 3.49 (m, 1H), 3.11 (t, 2H), 2.98 (d, 2H), 2.24 (m, 2H), 2.11 (m, 2H), 1.90-1.70 (m, 4H), 1.43-1.19 (m, 4H), 1.06 (m, 2H); MS (ESI) m / z: calc'd for C ₁₂ H ₂₅ N ₂ , 197.2; Found: 197.2 (M ⁺ +1).

Example 107

tert-butyl 1- (3,5-difluorobenzyl) piperidin-4-ylcarbamate

The title compound was obtained from tert-butyl piperidin-4-ylcarbamate (2 g, 10 m. Mol) and 3,5-difluorobenzaldehyde (1.42 g, 10 mmol) by the procedure described in Preparation 3. Prepared (3.3 g, 100%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.85 (m, 2H), 6.65 (m, 1H), 4.45 (bs, 1H), 3.50 (m, 1H), 3.05 (s, 2H), 2.75 (m , 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.45 (m, 11H). MS (ES1) m / z: calc .: 326.38; Measured value: 327.0 (M ⁺ +1).

Example 108

4-chloro-6-isopropylthieno [2,3-d] pyrimidine

The title compound was prepared from 6-isopropylthieno [2,3-d] pyrimidin-4-ol (15 g, 0.077 mol) by the procedure described in Preparation 2 (13 g, 80%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.80 (s, 1H), 7.10 (s, 1H), 3.30 (m, 1H), 1.45 (d, 6H). MS (ESI) m / z: calc .: 212.7; Measured value: 213.2 (M ⁺ +1).

Example 109

4-chloro-6-isobutylthieno [2,3-d] pyrimidine

The title compound was prepared from 4,6-isobutylthieno [2,3-d] pyrimidin-4-ol (1 g, 4.8 m.mol) by the procedure described in Preparation 2 (0.96 g, 88% ). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.95 (s, 1H), 7.10 (s, 1H), 2.80 (d, 2H), 2.05 (m, 1H), 1.05 (d, 6H). MS (ESI) m / z: calc .: 226.73; Found: 227.1 (M ⁺ +1).

Example 110

4-chloro-5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine

The title compound was prepared by 5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-ol (6.5 g, 32 mmol) by the procedure described in Preparation 2. ) (6.3 g, 90%). ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.71 (s, 1H), 3.10 (m, 2H), 2.89 (m, 2H), 1.94 (m, 4H); MS (SEI): m / z: Calculated value: 224; Measured value: 225 (M ⁺ +1).

Example 111

4-chloro-5,6-dimethyl-thieno [2,3-d] pyrimidine

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.81 (s, 1 H), 7.23 (s, 1 H), 2,67 (s, 3 H), 2.69 (s, 3 H). MS (ESI) m / z: calc .: 198.6; Measured value: 199.5 (M + 1).

Example 112

4-chloro-thieno [2,3-d] pyrimidine

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.88 (s, 1H), 7.65 (d, 1H), 7.48 (d, 1H). MS (ESI) m / z: Calculated value: 170.6; Found: 171.0 (M + 1).

Example 113

4,6-dichloro-5-methylthieno [2,3-d] pyrimidine

The title compound was prepared from 6-chloro-5-methylthieno [2,3-d] pyrimidin-4-ol (400 mg, 2.0 m.mol) by the procedure described in Preparation 2 (428 mg, 98 %). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.80 (s, 1 H), 2.65 (s, 3 H).

Example 114

6-isobutylthieno [2,3-d] pyrimidin-4-ol

The title compound was prepared from ethyl 2-amino-5-isobutylthiophen-3-carboxylate (4.68 g, 21 m. Mol) by the procedure described in Preparation 1 (3.58 g, 82%). ¹ H NMR (400 MHz, CD ₃ 0D): δ 8.50 (s, 1H), 7.20 (s, 1H), 2.80 (d, 2H), 1.95 (m, 1H), 1.00 (d, 6H). MS (ESI) m / z: calc .: 208.28; Measured value: 209.2 (M ⁺ +1).

Example 115

6-isopropylthieno [2,3-d] pyrimidin-4-ol

The title compound was prepared from ethyl 2-amino-5-isopropylthiophene-3-carboxylate (23.5 g, 0.11 mol) by the procedure described in Preparation 1 (15 g, 70%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (s, 1 H), 7.10 (s, 1 H), 3.00 (m, 1 H), 1.40 (d, 6 H). MS (ESI) m / z: Calculated value: 194.25; Measured value: 195.3 (M ⁺ +1).

Example 116

6-chloro-5-methylthieno [2,3-d] pyrimidin-4-ol

In a solution of 5-methylthieno [2,3-d] pyrimidin-4-ol (2 g, 12 m. Mol) in acetic acid (30 mL) at room temperature is bubbled with chlorine gas for 3 hours. The reaction mixture was stirred at the same temperature for 2 days. The solvent was evaporated at 40 ° C. under reduced pressure and the residue was dissolved in ethyl acetate (30 mL) and washed with saturated NaHCO ₃ solution (3 × 20 mL). The organic layer was dried over sodium sulfate and evaporated to afford the title compound as a pale yellow solid (2 g, 82%). ¹ H NMR (400 MHz, CDCl ₃ and CD ₃ 0D): δ 7.90 (s, 1H), 2.55 (s, 3H). MS (ESI) m / z: calc .: 200.65; Measured value: 201.3 (M ⁺ +1).

Example 117

6-chloro-5-methylthieno [2,3-d] pyrimidin-4-ol

The title compound was prepared from ethyl 2-amino-5-chloro-4-methylthiophen-3-carboxylate (5 g, 27 m.mol) by the procedure described in Preparation 1 (3.38 g, 75%) . ¹ H NMR (400 MHz, CD ₃ 0D): δ 8. 00 (s, 1H), 7.00 (s, 1H), 2.55 (s, 3H). MS (ESI) m / z: Calculated value: 166.2; Found: 167.1 (M ⁺ +1).

Example 118

Thieno [2,3-d] pyrimidin-4-ol

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.05 (s, 1 H), 7.53 (dd, 1 H), 7.33 (dd, 1 H). MS (ESI) m / z: Calculated value: 152.1; Measured value: 153.2 (M + 1).

Example 119

5,6 Dimethyl-thieno [2,3-d] pyrimidin-4-ol

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.00 (s, 1H), 2.63 (s, 3H), 2.61 (s, 3H). MS (ESI) m / z: Calculated value: 180.23; Measured value: 181.1 (M + 1)

Example 120

5,6,7,8-tetrahydro-benzo [4,5] -thieno [2,3-d] pyrimidin-4-ol

The title compound was prepared in 92% yield by the procedure described in Preparation 1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.35 (bs, 1H), 8.0 (s, 1H), 2.88 (t, 2H), 2.74 (t, 2H), 1.74 to 1.82 (m, 4H). MS (ESI) m / z: calc'd: 206.2; Measured value: 207.2 (M ⁺ +1).

General Synthesis of Piperidinylamino-thieno [2,3-d] pyrimidines

Ethyl 2-amino-3-carboxythiophene 2 was refluxed with ammonium formic acid and formamide to give cyclized intermediate 3 which was then treated with thionyl chloride to give chloride derivative 4. Boc-protected aminopiperidine 5 is reductively alkylated with various arylaldehydes 6 to provide the corresponding intermediate 7. Deprotection of 7 with trifluoroacetic acid treatment gave the free amine intermediate 8. Final compound 1 was obtained by refluxing the mixture of key intermediates 4 and 8 in i-propanol or acetonitrile in the presence of triethylamine.

The following compounds of the present invention prepared by the above synthetic method are expected to have good activity:

(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (4-trifluoromethyl-benzyl) -pi Ferridin-4-yl] -amine

(1-phenethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)- Amine

[1- (3-phenyl-propyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidine- 4-yl) -amine

Example 121

Compound activity

Compounds of the present invention are prepared according to the respective synthesis described above, and their activity and selectivity are determined. These compounds have been found to be active (eg, at concentrations of about 0.1 to about 10 μM) and to selective 5-HT _2B modulators. Test data are shown in Table 1. Therefore, it is guessed that such a compound is a serotonin excess or absence, e.g., 5-HT _2B receptor modulators in the treatment of a wide variety of clinical conditions that are characterized by serotonin sexual dysfunction or hyperactivity I useful. Such conditions include those associated with such recording and vascular diseases such as angina, migraine, pulmonary hypertension and systemic hypertension.

Equivalent

Those skilled in the art will recognize, or be able to ascertain, many equivalents to the specific procedures described herein using only routine assays. Such equivalents are considered to be within the scope of this invention and are within the scope of the appended claims. Various substitutions, changes, and variations may be made in accordance with the present invention without departing from the spirit and scope of the invention as defined by the claims. All references, published patents, and published patent applications cited throughout this application are incorporated herein by reference. Appropriate components, processes, and methods of these patents, applications, and other documents may be selected for the invention and embodiments of the invention.

Claims (32)

A compound of formula (I) and pharmaceutically acceptable salts and / or esters thereof: Formula I

Wherein R ₁ and R ₂ are independently hydrogen; Lower alkyl; C ₁ to C ₆ cycloalkyl or cycloheteroalkyl; Halogen or halo-substituted alkyl; Or R ₁ and R ₂ taken together form a C ₅ to C ₇ cycloalkyl or cycloheteroalkyl ring; Cy is a single or conjugated substituted or unsubstituted alicyclic ring or aromatic ring structure; And n is 0, 1, 2, 3, 4 or 5. The compound of claim 1, wherein R ₁ and R ₂ are taken together to form a C ₅ to C ₇ cycloalkyl or cycloheteroalkyl ring. The compound of claim 2, wherein R ₁ and R ₂ are taken together to form a cyclohexyl ring. The compound of claim 1, wherein n is 0, 1, 2 or 3. The compound of claim 1, wherein the lower alkyl is C ₁ -C ₅ alkyl. The compound of claim 1, wherein the compound is a 5-HT receptor antagonist. The compound of claim 6, wherein the compound is a 5-HT ₂ receptor antagonist. 8. The compound of claim 7, wherein the compound is a 5-HT _{2A , B or C} receptor antagonist. 8. The compound of claim 7, wherein the compound is a 5-HT _2B receptor antagonist. The compound of claim 1, wherein the compound is [1- (2-fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is [1- (3-fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is [1- (4-fluoro-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is [1- (4-methyl-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [ 2,3-d] pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is (1-benzo [1,3] dioxol-5-ylmethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4 , 5] thieno [2,3-d] pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is (5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (4- Trifluoromethyl-benzyl) -piperidin-4-yl] -amine. The compound of claim 1, wherein the compound is (1-benzhydryl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3- d] pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is (1-naphthalen-2-ylmethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2. , 3-d] pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is (1-phenethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d ] Pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is [1- (3-phenyl-propyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [ 2,3-d] pyrimidin-4-yl) -amine. The compound of claim 1, wherein the compound is (5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl)-[1- (4- Trifluoromethoxy-benzyl) -piperidin-4-yl] -amine. The compound of claim 1, wherein the compound is [1- (4-methoxy-benzyl) -piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo [4,5] thieno [2,3-d] pyrimidin-4-yl) -amine. Compounds of Formula II and pharmaceutically acceptable salts and / or esters thereof Formula II

Wherein R ₁ and R ₂ are independently hydrogen; Lower alkyl; C ₁ to C ₆ cycloalkyl or cycloheteroalkyl; Halogen or halo-substituted alkyl; Or R ₁ and R ₂ taken together form a C ₅ to C ₇ cycloalkyl or cycloheteroalkyl ring; R ₃ and R ₄ are independently Ar, which is a single or conjugated substituted or unsubstituted aromatic ring structure; R ₅ is H, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₆ ) cycloalkyl, halogen substituted alkyl, NH ₂ , NHMe, NMe ₂ , NHEt, NH (Et) ₂ , NH (Pr), N (Pr) ₂ ; And n is 0, 1, 2, 3, 4 or 5. A pharmaceutical composition comprising the compound of claim 1 in an amount effective for treating depression. A pharmaceutical composition comprising the compound of claim 1 in an amount effective for treating a CNS disease. A pharmaceutical composition comprising the compound of claim 1 in an amount effective to treat migraine headaches. A method of treating depression, comprising administering to a patient a pharmaceutical composition comprising the compound of claim 1 in an amount effective to treat depression. A method of treating CNS disease comprising administering to a patient a pharmaceutical composition comprising the compound of claim 1 in an amount effective to treat CNS disease. A method of treating CNS disease comprising diagnosing a patient in need of CNS treatment and administering to the patient a therapy comprising a pharmaceutical composition comprising the compound of claim 1 in an amount effective to treat CNS disease. A method of treating pulmonary hypertension comprising administering to a patient a pharmaceutical composition comprising the compound of claim 1 in an amount effective to treat pulmonary hypertension. A method of treating pulmonary hypertension comprising diagnosing a patient in need of pulmonary hypertension and administering to the patient a therapy comprising a pharmaceutical composition comprising the compound of claim 1 in an amount effective to treat pulmonary hypertension. A method of treating systemic hypertension comprising administering to a patient a pharmaceutical composition comprising the compound of claim 1 in an amount effective to treat systemic hypertension. A method of treating systemic hypertension comprising diagnosing a patient in need of treatment of systemic hypertension and administering to the patient a therapy comprising a pharmaceutical composition comprising the compound of claim 1 in an amount effective to treat systemic hypertension.